KR20090086604A - Antibacterial quinoline derivatives - Google Patents

Abstract

The present invention relates to novel substituted quinoline derivatives of formula (la) or formula (lb), or stereochemically isomeric, N-oxide forms, pharmaceutically acceptable salts or solvates thereof:

The claimed compound Useful for the treatment of bacterial infections. Also claimed is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a claimed compound as an active ingredient, the use of the claimed compound or composition for the manufacture of a medicament for the treatment of bacterial infection, and a method for preparing the claimed compound. do.

Description

Antimicrobial Quinoline Derivatives {ANTIBACTERIAL QUINOLINE DERIVATIVES}

The present invention is Mycobacterium tuberculosis Tudor beokyul (Mycobacterium tuberculosis), M. Bovis (M. Bovis), M. Le Prado (M. leprae), M. Oh Away (M. Avium) and M. Marie num (M and novel substituted quinoline derivatives useful for treating bacterial diseases including, but not limited to, pathogenic mycobacteria such as marinum ), or diseases caused by pathogenic staphylococci or streptococci.

Mycobacterium tuberculosis is a pathogen of tuberculosis (TB), a worldwide, serious and potentially fatal infection. The World Health Organization reports that more than 8 million people have TB every year and 2 million people die every year from tuberculosis. Over the past decade, TB cases have been the biggest concern worldwide, increasing by 20% in most poorer populations. If this trend continues, TB incidence will increase by 41% over the next 20 years. In the 50 years since the introduction of effective chemotherapy, TB remains behind AIDS, the leading infectious cause of adult death worldwide. Exacerbating the TB epidemic is an updraft of multidrug resistant strains and a lethal symbiosis of HIV. People who are HIV-positive and infected with TB are about 30 times more likely to develop active TB than people who are HIV-negative, and TB causes death in one in three people with HIV / AIDS worldwide.

Current approaches to treating tuberculosis include combinations of all multiple drugs. For example, the therapy recommended by the US Public Health Administration is the combination of isoniazid, rifampicin and pyrazineamide for two months, followed by an additional four months of isoniazid and rifampicin alone. These drugs continue for an additional seven months in patients infected with HIV. For patients infected with multidrug resistant strains of M. tuberculosis, agents such as etambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, cipropoxacin, and oploxacin are combined therapy. It is used together. There is no single agent effective for the clinical treatment of tuberculosis, and no drug combination exists that provides therapeutic potential for less than six months.

There is a high demand in the medical community for new drugs that enable therapies that promote compliance of patients and providers, thereby improving current therapies. Shorter durations and less management are the best ways to achieve this. The maximum benefit from the therapy appears within the first two months during the intensive, or sterilization phase, in which the four drugs are given together; The amount of bacteria present is significantly reduced and the patient becomes noninfectious. A 4- to 6-month extension, or sterilization step, is required to remove residual bacteria and minimize the risk of recurrence. Stabilizing drugs that are effective in shortening treatment to less than two months would be very beneficial. There is also a need for drugs that promote compliance by requiring less intensive care. Clearly, compounds that can shorten the overall treatment period and reduce the number of drug administrations will provide the greatest benefit.

Deterioration of the TB epidemic will increase the incidence of multidrug resistant strains or MDR-TB. MDR-TB, which is resistant to the four most potent drugs, isoniazid and rifampin, is believed to be less than 4% in all cases worldwide. Therapy requires a "second-line" drug for up to two years because MDR-TB is fatal when not treated and cannot be properly treated through standard therapies. These drugs are mainly toxic, expensive and slightly effective. In the absence of an effective treatment, infectious MDR-TB patients continue to spread the disease and thereby form new infections with the MDR-TB strain. In particular, new drugs with new mechanisms of action capable of demonstrating activity against MDR strains are highly desired in the medical community.

"Drug resistance" as used above or later is a term well known to microbialists. Drug resistant mycobacteria are mycobacteria that have expressed their ability to withstand antibiotic attacks by at least one previously effective drug by no longer being sensitive to at least one previously effective drug. Drug resistant strains can propagate their ability to withstand descendants. The resistance may be due to free genetic variation in bacterial cells that alter sensitivity to a single drug or to different drugs.

MDR tuberculosis is a specific form of drug resistant tuberculosis caused by bacteria that is at least resistant to isoniazid and rifampicin (with or without other drugs), and these drugs are currently the two most potent anti-TB drugs. Thus, whenever used above or later, "drug resistance" includes multiple drug resistance.

Another factor in controlling pandemic TB is the latent problem of TB. Despite decades of tuberculosis (TB) control system, about 20 million people are infected with M. tuberculosis without asymptomatic symptoms. About 10% of individuals are at risk of developing active TB while they are alive. The global prevalence of TB is accelerating with TB infection in HIV patients and the development of multiple drug resistant TB strains (MDR-TB). Reactivation of latent TB is a very dangerous factor for disease development and accounts for 32% of deaths from HIV infection. In order to control pandemic TB, new drugs have to be developed that can combat dormant or latent Bacillus. Resting TB can be reactivated by the use of immunosuppressants such as antibodies to cancer necrosis factor α or interferon-γ to cause disease by a number of factors, such as host immunity inhibition. For HIV positive patients, the only prophylactic treatment acceptable for latent TB is a two to three month regimen of rifampicin, pyrazinamide. The efficacy of this treatment regimen is still unclear, and the duration of treatment is an important pressure in a resource-limited environment. Therefore, it is urgent to find new drugs that can act as chemopreventive agents in individuals with potential TB Bacillus.

Tubercle bacilli enter into healthy individuals by inhalation and are predated by alveolar macrophages in the lungs. This results in a strong immune response and granulomatous formation consisting of macrophages infected with M. tuberculosis surrounded by T cells. After 6-8 weeks, the host immune response kills the infected cells and accumulates macrophages, epithelial cells and casein material with specific extracellular Bacillus surrounded by a lymphatic tissue layer at the periphery. In healthy individuals, most mycobacteria die in this environment, but a small number of Bacillus are still viable, non-replicating and metabolic, and are believed to survive intact with anti-TB drugs such as isoniazid. These Bacillus may be present without any clinical disease symptoms while living in an altered physiological environment. However, 10% of these latent Bacillus become reactive and cause disease. There is one hypothesis that these persistent bacteria can develop due to the pathological-physiological environment in human lesions: reduced oxygen partial pressure, nutritional restriction and acidic pH. It can be assumed that these factors make the bacteria phenotypicly resistant to the main anti-mycobacterial drug.

Besides pandemic TB management, the problem of resistance to first-generation antibiotics is emerging. Penicillin-resistant Streptococcus pneumoniae as some important examples (Streptococcus pneumoniae), vancomycin-resistant Enterococcus cock when (enterococci), methicillin-resistant Staphylococcus aureus (Staphylococcus aureus ), and multidrug-resistant salmonellae .

The consequences of antibiotic resistance are serious. Infection with resistant microorganisms renders them unresponsive to treatment, leading to prolonged illness and increased risk of death. Treatment failures also increase the duration of infection, increasing the number of infected populations in the community, which puts the general population at risk of contact with resistant strain infections. Hospitals are a major contributor to antimicrobial resistance issues worldwide. The combination of highly susceptible patients, intensive use of long-term antimicrobials and cross infection results in infection with highly resistant bacterial pathogens.

Self-treatment of antimicrobial agents is another major factor contributing to resistance. Self-treatment of antimicrobial agents may be unnecessary and may often be inappropriately administered or may not contain an appropriate amount of active drug.

Patient compliance with recommended treatment is another major factor. The patient may forget to take the drug, may stop his treatment when the condition begins to improve, or may not be able to go through the whole process, creating an ideal environment for adapting rather than killing the microorganisms.

With the advent of multiple antibiotic resistance, doctors faced infections without effective treatment. The morbidity, mortality, and financial costs of these infections are becoming obstacles to health care systems worldwide.

Thus, there is a strong desire for new compounds to treat bacterial infections, including drug resistant and latent mycobacterial infections, in particular mycobacterial infections and other bacterial infections caused by particularly resistant bacterial strains.

WO 2004/011436, WO2005 / 070924, WO2005 / 070430 and WO2005 / 075428 describe certain substituted quinoline derivatives that show activity against mycobacteria, in particular mycobacterium tuberculosis. WO2005 / 117875 describes substituted quinoline derivatives that are active against resistant mycobacterial strains. WO2006 / 067048 describes substituted quinoline derivatives that are active against latent tuberculosis. One particular compound of these substituted quinoline derivatives is described in Science (2005), 307, 223-227, the mode of action of which is described in WO2006 / 035051.

Other substituted quinolines are described in US Pat. No. 5,965,572 (US) for the treatment of antibiotic resistant infections and WO 00/34265 for the inhibition of the proliferation of bacterial microorganisms.

It is an object of the present invention, in particular, to inhibit bacterial growth of mycobacteria and other bacteria, such as streptococci and staphylococci, and therefore, bacterial diseases, in particular Streptococcus pneumonia , Staphylococcus aureus ( Staphylococcus aureus) or Mycobacterium tuberculosis Tudor beokyul (Mycobacterium tuberculosis; including latent diseases and drug resistant M. tuberculosis strains), M. bovis (M. bovis), M. Le Prado (M. leprae), M. O It is to provide novel compounds, especially substituted quinoline derivatives, useful for the treatment of diseases caused by pathogenic bacteria such as M. avium and M. marinum .

[Summary of invention]

The present invention relates to novel substituted quinoline derivatives of formula (la) or (lb), or stereochemically isomeric, N-oxide forms, pharmaceutically acceptable salts or solvates thereof:

Where

q is an integer of 0, 1, 2, 3 or 4;

p is an integer of 1, 2, 3 or 4;

R ¹ is alkenyl, alkynyl, -C = N-OR ¹¹ , amino, mono or di (alkyl) amino, aminoalkyl, mono or di (alkyl) aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl, mono Or di (alkyl) aminocarbonyl, arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-;

R ² is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino, pyrrolidino or a radical of the formula:

,

Wherein Y is CH ₂ , O, S, NH or N-alkyl;

R ³ is alkyl, arylalkyl, aryl-O-alkyl, aryl-alkyl-O-alkyl, aryl, Het, Het-alkyl, Het-O-alkyl, Het-alkyl-O-alkyl or Is;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl;

R ⁴ and R ⁵ together with N to which they are attached include alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl And pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, already optionally substituted with pyrimidinyl Consisting of dazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Can form radicals selected from the group;

R ^4a and R ^5a together with the nitrogen atom to which they are attached are alkyl, haloalkyl, halo, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, Pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2, optionally substituted by 1, 2, 3 or 4 substituents independently selected from pyridyl or pyrimidinyl 3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azinyl, hexahydro-1H-1,4- Diazepinyl, hexahydro-1,4-oxazepineyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2- Consisting of imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl Form a radical selected from the group, and;

R ⁶ is aryl ¹ or Het;

R ⁷ is hydrogen, halo, alkyl, aryl or Het;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =;

R ¹¹ is hydrogen or alkyl;

Aryl is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono Or a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from dialkylaminocarbonyl;

Aryl ¹ is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, alkylthio, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, mor A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from polyyl, Het or mono- or dialkylaminocarbonyl;

Het is N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl Monocyclic heterocycles selected from pyrazinyl or pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [ Bicyclic heterocycle selected from 1,4] dioxylyl or benzo [1,3] dioxolyl; Wherein each monocyclic and bicyclic heterocycle is optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, alkyl or alkyloxy.

Whenever used herein, the term "compound of formula (la) or (lb)" or "compound of the invention" is meant to include its pharmaceutically acceptable salt or N-oxide forms or solvates.

For example, a compound of formula (Ia) and a formula in that the compound of formula (Ib) wherein R ⁹ is oxo is a tautomer equivalent (keto-enol tautomerization) of the compound of formula (Ia) wherein R ² is hydroxy The compounds of (lb) are interrelated.

In the definition of Het, it is meant to include all possible isomers of the heterocycle, for example pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl.

Aryl, aryl ¹ or Het (see eg R ³ ) listed in the substituent definitions of the compounds of formula (Ia) or (Ib), referred to above or later, may optionally be any ring carbon or heteroatom, unless otherwise specified. Through the remainder of the molecule of formula (la) or (lb). Thus, for example, when Het is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

Lines drawn from the substituents into the ring system indicate that the bond may be attached to any suitable ring atom.

Pharmaceutically acceptable salts, referred to above or hereinafter, are meant to include therapeutically active non-toxic acid addition salt forms which the compounds of formula (la) or (lb) may form. Base forms of the compounds of formula (la) or (lb) may be selected from suitable acids, such as inorganic acids, such as hydrochloric acid, such as hydrochloric acid, hydrobromic acid; Sulfuric acid; nitric acid; And phosphoric acid; Organic acids such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene The acid addition salts can be obtained by treatment with sulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Compounds of formula (la) or (lb), including acidic protons, can be converted to their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Pharmaceutically acceptable salts, referred to above or hereinafter, also include therapeutically active non-toxic metal or amine addition salt forms (basic addition salt forms) that the compounds of formula (la) or (lb) may form. Means that. Suitable base addition salt forms are, for example, ammonium salts, alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases such as methylamine, ethylamine, propyl Amine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, Trimethylamine, triethylamine, tripropylamine, quinuclidin, pyridine, quinoline and isoquinoline, benzatin, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3- Salts with primary, secondary and tertiary aliphatic and aromatic amines, such as propanediol, hydrabamine salts, and amino acids such as, for example, arginine, lysine.

In contrast, acid or base addition salt forms can be converted to the free form by treatment with an appropriate base or acid.

The term "pharmaceutically acceptable salts" is also general formula (Ia) or (Ib) of the basic nitrogen compound with a suitable quaternary agent, for example an optionally substituted C ₁ of the _6-alkyl halides, aryl C _1-6 alkyl halide, C _1-6 alkylcarbonyl halide, arylcarbonyl halide, HetC _1-6 alkyl halide or Het carbonyl halide, for example, by reaction between methyl iodide or benzyl iodide, of formula (Ia) or (Ib) Quaternary ammonium salts (quaternary amines) that the compounds may form. Preferably, Het is a monocyclic heterocycle selected from furanyl or thienyl; Or a bicyclic heterocycle selected from benzofuranyl or benzothienyl; Each monocyclic and acyclic heterocycle may be optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, alkyl and aryl, respectively. Preferably, the quaternizing agent is C _1-6 alkyl halide. Other reactants with good leaving groups such as C _1-6 alkyl trifluoromethanesulfonate, C _1-6 alkyl methanesulfonate and C _1-6 alkyl p-toluenesulfonate can also be used. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. Preferably, the counterion is iodo. The counterion selected can be introduced using an ion exchange resin.

The term “solvate” also includes solvates and solvent addition forms, and salts thereof, which the compounds of formula (la) or (lb) can form. Examples of such forms are, for example, hydrates, alcoholates and the like.

In the context of the present application, the compounds of the present invention are intended to include essentially all of their stereochemical isomers. The term “stereochemical isomer” as used above or hereinafter is defined as all possible stereoisomers that compounds of formulas (Ia) and (Ib), and their N-oxides, pharmaceutically acceptable salts or physiological functional derivatives may have. do. Unless otherwise stated or indicated, the chemical nomenclature of a compound refers to a mixture of all possible stereochemical isomers. In particular, the stereogenic center may have an R- or S-configuration; Bivalent cyclic (partially) saturated radicals are substituents on the cis (cis) - can have a coordination-or trans (trans). Compounds comprising a double bond may have an E (entgegen) or Z (jusamen) -stereochemistry at the double bond. The terms "cis", "trans", "R", "S", "E" and "Z" are known to those skilled in the art. Stereochemically isomers of the compounds of formulas (la) and (lb) are expressly intended to be included within the scope of this invention. Of particular interest are the compounds of formula (Ia) or (Ib) which are stereochemically pure.

According to the CAS nomenclature provisions, if there are two stereocenters of known absolute configuration, the R or S descriptor (based on the Cahn-Ingold-Prelog alignment rule) is designated as the lowest numbered chiral center. The coordination of the second stereoscopic center is expressed using the relative descriptors [R *, R *] or [R *, S *] (where R * is always specified as the reference center and [R *, R *] is Centers having the same chirality and [R *, S *] represent centers having different chirality). For example, if the lowest numbered chiral center in a molecule has an S configuration and the second center is R, the steric descriptors are described as S- [R *, S *]. When "α" and "β" are used, the position of the priority substituent on the asymmetric carbon atom of the ring system having the lowest ring number is always "α" of the mean plane determined by the ring system. Present in the position. The position of the most preferred substituent on another asymmetric carbon atom in the ring system with respect to the position of the most preferred substituent on the reference atom is "α" when present on the same side of the average plane determined by the ring system, or by the ring system When present on the other side of the determined mean plane, it is named "β".

When referring to specific stereoisomers, this means that the form is substantially free of other isomer (s), that is, less than 50%, preferably less than 20%, more preferably less than 10% with other isomer (s). , Even more preferably less than 5%, even more preferably less than 2% and most preferably less than 1%. Thus, when a compound of formula (la) or (lb) is specified, for example as (R, S), it means that the compound is substantially free of the (S, R) isomer.

The compounds of formula (la) or (lb) and some intermediate compounds have at least two stereogenic centers in their structures which can necessarily lead to at least four stereochemically different structures.

The compounds of formulas (Ia) and (Ib) can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures, which can be separated from one another according to known partitioning procedures. The racemic compounds of formulas (la) and (lb) can be converted into the corresponding diastereomeric salt forms by reaction with the appropriate chiral acid. The diastereomeric salt forms are then separated, for example by selective or fractional crystallization, from which enantiomers are released by alkyli. Another method of separating the enantiomeric forms of the compounds of Formulas (Ia) and (Ib) includes liquid chromatography using chiral stationary phases. The pure stereochemical isomers may also be derived from the corresponding pure stereochemical isomers of the appropriate starting materials if the reaction takes place stereospecifically. Preferably, if specific stereoisomers are desired, the compounds may be synthesized by stereospecific methods of preparation. These methods advantageously utilize enantiomerically pure starting materials.

Tautomers of compounds of formula (Ia) or (Ib) are meant to include compounds of formula (Ia) or (Ib) in which, for example, the enol group is converted (keto-enol tautomerized) to a keto group. Tautomers of the compounds of formulas (Ia) and (Ib) or tautomers of the intermediates of the invention are intended to be encompassed by the scope of the invention.

The N-oxide form of the compounds is meant to include compounds of formula (la) or (lb) in which one or several tertiary nitrogen atoms are oxidized to so-called N-oxides.

Compounds of formulas (Ia) and (Ib) can be converted to the corresponding N-oxides according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of the formula (Ia) or (Ib) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkyl metal or alkyl earth metal peroxides such as sodium peroxide, potassium peroxide; Suitable organic peroxides are, for example, benzenecarboperoxoic acid or benzenecarboperoxoacids substituted with halo, such as 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acid, such as peroxoacetic acid, alkylhydroperoxides, such as and peroxy acid, such as t-butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

In the context of the present application, the compounds of the present invention are intended to include essentially all isotopic mixtures of their chemical elements. In the constitution of the present application, the chemical elements, especially when denoted with respect to compounds of formula (Ia) or (Ib), are all isotopically present in naturally occurring or synthetically produced, naturally occurring or isotopically enriched form. Elements and isotopic mixtures of these elements. In particular, where hydrogen is indicated, it is understood to mean ¹ H, ² H, ³ H and mixtures thereof; When carbon is indicated, it is understood to mean ¹¹ C, ¹² C, ¹³ C, ¹⁴ C and mixtures thereof; When nitrogen is indicated, it is understood to mean ¹³ N, ¹⁴ N, ¹⁵ N and mixtures thereof; When oxygen is indicated, it is understood to mean ¹⁴ 0, ¹⁵ 0, ¹⁶ O, ¹⁷ O, ¹⁸ O and mixtures thereof; When fluorine is indicated, it is understood to mean ¹⁸ F, ¹⁹ F and mixtures thereof.

Accordingly, the compounds of the present invention also include compounds having one or more isotopes of one or more elements and mixtures thereof, including radioactive compounds, also called radiolabeled compounds, in which one or more non-radioactive atoms are substituted into one of its radioisotopes. do. The term "radioactive labeling compound" means a compound of formula (la) or (lb), a pharmaceutically acceptable salt or N-oxide form or solvate thereof, containing at least one radioactive atom. For example, the compound may be labeled with a positron or gamma radiation radioactive isotope. In the radioligand binding method (membrane receptor measurement), the ³ H atom or ¹²⁵ I atom is the selected atom to be substituted. For imaging, the most commonly used positron emission (PET) radioisotopes are ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, all of which are produced accelerators, with half-lives of 20, 100, 2 and 10 minutes respectively. to be. Since the half-lives of these radioisotopes are too short, they can be used only in facilities with accelerators at their production sites, thus limiting their use. The most widely used of these are ¹⁸ F, ^{99 m} Tc, ²⁰¹ Tl and ¹²³ I. Handling of these radioisotopes, their production, separation and incorporation in the molecule are known to those skilled in the art.

In particular, the radioactive atom is selected from the group consisting of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is selected from the group consisting of hydrogen, carbon and halogen.

In particular, the radioisotope is selected from the group consisting of ³ H, ¹¹ C, ¹⁸ F, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Preferably, the radioisotope is selected from the group consisting of ³ H, ¹¹ C and ¹⁸ F.

In the context of the present application, alkyl is a straight or branched saturated hydrocarbon radical having 1 to 6 carbon atoms; Cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms bonded to linear or branched saturated hydrocarbon radicals having 1 to 6 carbon atoms; Each carbon atom may be optionally substituted with cyano, hydroxy, C _1-6 alkyloxy or oxo. Preferably alkyl is a straight or branched saturated hydrocarbon radical having 1 to 6 carbon atoms; Cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Each carbon atom is hydroxyl or C _{1 - 6} alkyl may be optionally substituted with aryloxy. Preferably, alkyl is methyl, ethyl or cyclohexylmethyl, more preferably methyl or ethyl.

The main embodiments of alkyl in all definitions used above or later are C _1-6 alkyl, for example methyl, ethyl, propyl, which represent straight or branched saturated hydrocarbon radicals having 1 to 6 carbon atoms. 2-methyl-ethyl, pentyl, hexyl and the like. Preferred subgroups of C _1-6 alkyl are C _1-4 alkyl which represent straight or branched saturated hydrocarbon radicals having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In the structure of this application, C _{2 - 6} alkenyl carbon atoms containing a double bond of 2 to 6, a straight-chain or branched hydrocarbon radical, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl or the like ; C _2-6 alkynyl is a straight or branched hydrocarbon radical having 2 to 6 carbon atoms including triple bonds such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C _3-6 cycloalkyl is a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms and is a generic term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In the configuration of the present application, halo is a substituent selected from the group consisting of fluoro, chloro, bromo and iodo, and haloalkyl is a linear or branched saturated hydrocarbon radical having 1 to 6 carbon atoms, a carbon atom number Cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms, or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms bonded to linear or branched saturated hydrocarbon radicals having 1 to 6 carbon atoms; One or more carbon atoms are substituted with one or more halo atoms. Preferably, halo is bromo, fluoro or chloro; Especially chloro or bromo. Preferably, haloalkyl is _{polyhaloC 1-6} alkyl defined as mono- or polyhalosubstituted C _1-6 alkyl, for example methyl having one or more fluoro atoms, for example di Fluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl and the like. When coupled to an alkyl group or a C _1-6 alkyl group within the definition of C _1-6 alkyl with one or more halo atoms or a haloalkyl poly be there, it may be the same or different.

The first main embodiment,

R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, -C = N-OR ¹¹ , amino, mono or di (C _1-6 alkyl) amino, aminoC _1-6 alkyl, mono or di ( C _1-6 alkyl) aminoC _1-6 alkyl, C _1-6 alkylcarbonylaminoC _1-6 alkyl, aminocarbonyl, mono or di (C _1-6 alkyl) aminocarbonyl, arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-;

R ² is hydrogen, C _1-6 alkyloxy, aryl, aryloxy, hydroxy, mercapto, C _1-6 alkyloxyC _1-6 alkyloxy, C _1-6 alkylthio, mono or di (C _{1- 6} alkyl) amino, pyrrolidino or a radical of the formula

,

Here, Y is CH _2, O, S, NH or NC _{1 - 6} alkyl;

R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, aryl C _1-6 alkyl, aryl, -OC _1-6 alkyl, aryl C _1-6 -OC _1-6 alkyl, aryl, Het, Het-C _1-6 alkyl, Het-OC _1-6 alkyl, HetC _1-6 alkyl-OC _1-6 alkyl or Is;

R ⁴ and R ⁵ are each independently hydrogen, C _{1 - 6} alkyl or benzyl;

And R ⁴ and R ⁵ together with N to which they are attached, include C _1-6 alkyl, halo, haloC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, amino, mono- or di ( Pyrrolidinyl optionally substituted with C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkylthioC _1-6 alkyl and pyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl A radical selected from the group consisting of pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl;

R ^4a and R ^5a together with the nitrogen atom to which they are bonded, respectively, C _{1 - 6} alkyl, C _{1- 6} alkyl, halo, aryl, C ₁ to be _poly-6 alkyl, hydroxy, C _{1 - 6} alkyloxy, C _{1 - 6} alkyloxy C _{1 - 6} alkyl, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 AlkylthioC _1-6 pyrrolidino, piperidino, piperazino, morpholino optionally substituted by 1, 2, 3 or 4 substituents independently selected from alkyl, aryl, pyridyl or pyrimidinyl , 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azinyl , Hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imi Dazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, Forms a radical selected from the group consisting of pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;

R ⁶ is aryl ¹ or Het;

R ⁷ is hydrogen, halo, C _{1 - 6} alkyl, aryl or Het is;

R ⁸ is hydrogen or C _{1 - 6} alkyl, and;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =;

R ¹¹ is hydrogen or C _{1 - 6} alkyl, and;

Each aryl is hydroxy, halo, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _{1 - 6} alkyl, C ₁ to be _poly-6 alkyl, C _{1 - 6} alkyloxy, halo C _{1 - 6} alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or di (C _1-6 alkyl) aminocarbonyl 1 is independently selected from carbonyl, or 2 A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by three substituents;

Aryl ¹ is hydroxy, halo, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy , C _1-6 alkylthio, haloC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl, Het or mono- or di (C _1-6 alkyl) aminocarbon A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from niyl;

Het is N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl Monocyclic heterocycles selected from pyrazinyl or pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [ Bicyclic heterocycle selected from 1,4] dioxylyl or benzo [1,3] dioxolyl; Wherein each monocyclic and bicyclic heterocycle is a major embodiment optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkyloxy As a compound of formula (Ia) or (Ib) as described above or a subgroup thereof.

A second major embodiment is wherein R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, —C═N—OR ¹¹ , amino, mono or di (C _1-6 alkyl) amino, aminoC _1-6 Alkyl, mono or di (C _1-6 alkyl) aminoC _1-6 alkyl, C _1-6 alkylcarbonylaminoC _1-6 alkyl, aminocarbonyl, mono or di (C _1-6 alkyl) aminocarbonyl , Arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (═O) —; In particular R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, —C═N—OR ¹¹ , R ^5a R ^4a Nalkyl, R ^5a R ^4a N— or R ^5a R ^4a NC (═O) — Is; In particular the main embodiments wherein R ¹ is C _2-6 alkenyl or —C═N—OR ¹¹ , relate to the compounds of formula (la) or (lb) described above or subgroups thereof.

The third main embodiment relates to a compound of formula (la) or (lb) or a subgroup thereof, as the main embodiment wherein p is one.

A fourth main embodiment is a compound of formula (Ia) or (Ib) as described above as the main embodiment wherein R ² is hydrogen, alkyloxy or alkylthio, in particular hydrogen, C _1-6 alkyloxy or C _1-6 alkylthio Or to a subgroup thereof. In particular, R ² is C _1-6 alkyloxy, preferably methyloxy.

A fifth major embodiment is a compound wherein R ³ is alkyl, arylalkyl, aryl, or Het; In particular C _1-6 alkyl, arylC _1-6 alkyl, aryl, or Het; In particular C _1-6 alkyl, optionally substituted phenyl, optionally substituted naphthyl, aryl C _1-6 alkyl, wherein aryl represents optionally substituted phenyl or optionally substituted naphthyl, or Het; In particular optionally substituted phenyl, optionally substituted naphthyl, or aryl-C _{1 - 6} alkyl (wherein aryl represents an optionally substituted phenyl or optionally substituted naphthyl), and; Optional substituents preferably relate to a compound of formula (la) or (lb) or a subgroup thereof as described above as the main embodiment which is halo, for example chloro. Preferably, R ³ is phenyl; Naphthyl; Phenyl C _{1 - 6} alkyl, a _{- 6} alkyl or naphthyl C _1.

The sixth main embodiment relates to a compound of formula (la) or (lb) or a subgroup thereof as described above as the main embodiment wherein q is 1, 2 or 3. In particular, q is 1 or 3.

The seventh main embodiment is of the general formula (Ia) or (Ib) described above as the main embodiment wherein R ⁴ and R ⁵ each independently represent hydrogen or C _1-6 alkyl, in particular C _1-6 alkyl, in particular methyl or ethyl To a compound of or a subgroup thereof. Preferably R ⁴ and R ⁵ are methyl.

Eighth major embodiment is piperidino, piperazino, morpholino, imidazolyl and triazolyl, each of which R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are optionally substituted with C _1-6 alkyl A radical selected from the group consisting of; In particular, the main embodiment for forming piperidino relates to a compound of formula (la) or (lb) or a subgroup thereof.

A ninth major embodiment is phenyl wherein R ⁶ is optionally substituted with halo, cyano or C _1-6 alkyloxy; In particular the main embodiments, which are phenyl optionally substituted with halo, relate to the compounds of formula (la) or (lb) described above or subgroups thereof.

The tenth main embodiment relates to a compound of formula (Ia) or (Ib) or a subgroup thereof as described above, wherein R ⁷ is hydrogen.

The eleventh main embodiment relates to a compound of formula (la) or (lb) or a subgroup thereof as described above, wherein the compound is a compound of formula (la).

A twelfth major embodiment relates to the aforementioned compound of formula (la) or (lb) or a subgroup thereof as the main embodiment wherein the compound is a compound of formula (lb), R ⁸ is hydrogen, and R ⁹ is oxo. .

A thirteenth major embodiment is the above-mentioned formula (Ia) or (Ib) as the main embodiment wherein the compound is a compound of formula (Ib), in particular R ⁸ is alkyl, more preferably C _1-6 alkyl, for example methyl. ) Or a subgroup thereof.

A fourteenth main embodiment relates to a compound of formula (la) or (lb) or a subgroup thereof as described above as the main embodiment wherein R ¹ is located at position 6 of the quinoline ring. In the context of the present application, the quinoline ring of the compound of formula (la) or (lb) is numbered as follows:

.

Fourteenth major embodiments provide that each of the aryls is halo, for example chloro; Cyano; Alkyl such as methyl; Or alkyloxy, for example naphthyl or phenyl optionally substituted with one or two substituents selected from methyloxy, more preferably phenyl; the compounds of formula (Ia) or (Ib) as described above as main embodiments; It's about subgroups.

A fifteenth major embodiment is of the general formula (Ia) or (I) described above as a main embodiment for the manufacture of a medicament for the treatment of bacterial infection by Gram-positive and / or Gram-negative bacteria, preferably bacterial infection by The use of a compound of Ib) or a subgroup thereof.

A sixteenth major embodiment is directed to a compound of formula (la) or (lb) wherein IC ₉₀ <15 μl / ml for at least one bacterium, in particular Gram-positive bacteria; Preferably IC ₉₀ <10 μl / ml; More preferably, to prepare a medicament for the treatment of bacterial infections having an IC ₉₀ <5 μl / ml (IC ₉₀ values are measured as described below) of the formulas (Ia) or (Ib) To the use of a compound or a subgroup thereof.

A seventeenth major embodiment relates to a compound of formula (la) or (lb) or a subgroup thereof as described above as the main embodiment to which one or more, preferably all of the following definitions apply:

R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, -C = N-OR ¹¹ , amino, aminoC _1-6 alkyl, mono or di (C _1-6 alkyl) aminoC _1-6 alkyl , C _1-6 alkylcarbonylaminoC _1-6 alkyl, mono or di (C _1-6 alkyl) aminocarbonyl, arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-;

R ² is alkyloxy, in particular C _{1 - 6} alkyloxy, preferably methyloxy, and;

R ³ is arylalkyl or aryl; In particular phenyl, naphthyl or phenylC _1-6 alkyl optionally substituted with halo;

R ⁴ and R ⁵ is C _{1 - 6} alkyl; Especially methyl; R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, form piperidino;

R ⁶ is phenyl optionally substituted with halo,

R ⁷ is hydrogen;

R ¹¹ is hydrogen or C _{1 - 4} alkyl; In particular hydrogen or methyl;

q is 1 or 3;

p is 1.

Preferably, in the above-described compounds of the formulas (Ia) and (Ib) or subgroups thereof as the main embodiments, the term "alkyl" denotes C _1-6 alkyl, more preferably C _1-4 alkyl, The term "haloalkyl" refers to polyhaloC _1-6 alkyl.

Most preferred compounds of formula (Ia) are compounds selected from compounds of the formula: stereochemical isomers, pharmaceutically acceptable salts, N-oxides or solvates thereof:

.

In particular, preferred compounds of formula (la) are compounds 7, 33, 9 or 34 (see table below); Or a pharmaceutically acceptable salt, N-oxide form or solvate thereof.

Preferably, the compound of formula (la) or (lb) is a particular mixture of enantiomers (hereinafter referred to as specific A or B diastereoisomers) and therefore substantially free of other diastereoisomer (s). . If the compound of formula (la) or (lb) has two chiral centers, it is a mixture of (R, S) and (S, R) enantiomers, in particular racemic mixtures or (R, R) And (S, S) enantiomers, in particular racemic mixtures. In the following, a mixture of two enantiomers, in particular a racemic mixture, is referred to as diastereo isomer A or B. Whether the racemic mixture is represented by A or B depends on whether it is separated first in the synthesis protocol (ie A) or second (ie B). More preferably, the compound of formula (la) or (lb) is a particular enantiomer (substantially free of other enantiomers). If a compound of formula (la) or (lb) has two chiral centers, it is a compound (R, S), (S, R), (R, R) or (S, S) enantiomer it means. Below, specific enantiomers are represented as A1, A2, B1 or B2. Enantiomers represented by A1, A2, B1 or B2 can be separated first or second in the synthesis protocol (1 or 2), or separated into A (A1, A2) or B (B1, B2) diastereoisomers. It depends.

Pharmacology

The compounds of the present invention are surprisingly particularly notable for mycobacterial diseases, including mycobacterial tuberculosis (including its latent and drug resistant forms), M. bovis, M. lepra, M. avium and M. marinum. It has been shown to be suitable for the treatment of bacterial diseases, including those caused by pathogenic mycobacteria. Accordingly, the present invention also provides a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for use as a medicament for the treatment of bacterial infections, including mycobacterial infection. , N-oxide form or solvate.

The present invention also provides a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt, N-oxide form or solvate thereof, for the manufacture of a medicament for the treatment of bacterial diseases, including mycobacterial diseases, And the use of the pharmaceutical compositions described above for the manufacture of a medicament for the treatment of bacterial infections, including mycobacterial infections.

Thus, in another aspect, the present invention provides a method of treating a patient suffering from or at risk of a bacterial disease, including a mycobacterial disease, comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the present invention. Provide a method.

In addition to activity against mycobacteria, the compounds of the present invention are also active against other bacteria. In general, bacterial pathogens can be classified as either gram positive or gram negative. Antibiotic compounds that are active against both Gram-positive and Gram-negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are considered to be active against gram positive and / or gram negative bacterial pathogens, in particular gram positive bacterial pathogens. In particular, the compounds of the present invention are active against at least one Gram-positive bacteria, preferably some Gram-positive bacteria, more preferably one or more Gram-positive bacteria and / or one or more Gram-negative bacteria.

The compound of the present invention has bactericidal or bacteriostatic activity.

As examples of Gram-positive and Gram-negative aerobic and anaerobic bacteria, Staphylococci, for example S. aureus ; Enterocoxy, for example E. faecalis ; Streptococci, for example S. pneumoniae , S. mutans , S. pyogens ; Vasily, for example Bacillus subtilis ; Listeria, for example Listeria monocytogene s; Haemophilus, for example H. influenz a; Moraxella, for example M. catarrhalis ; Pseudomonas, for example Pseudomonas aeruginosa ; And Escherichia, for example E. coli . Gram-positive pathogens, such as staphylococci, enterococci and streptococci, for example, are particularly important because they express resistant strains that are difficult to treat as well as difficult to eradicate from once established hospital environments. One example of such a strain is methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multidrug-resistant Enterococcus faecium .

The compounds of the present invention also show activity against resistant bacterial strains.

Compounds of the invention are particularly useful for example, such as methicillin resistant Staphylococcus aureus (MRSA). It is active against Staphylococcus aureus and Streptococcus pneumoniae , including resistant Staphylococcus aureus . The compounds of the present invention are particularly active against Streptococcus pneumoniae .

Accordingly, the present invention also provides for the treatment of bacterial infections, including infections of compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, N-oxide forms or solvates, and staphylococci and / or streptococci. It relates to the use of a pharmaceutical composition described above for the manufacture of a medicament for treatment.

Thus, in another aspect, the invention suffers from or is at risk of a bacterial infection, including infection with staphylococcus and / or streptococci, comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention. It provides a method of treating a patient with this condition.

Without being bound by theory, the activity of the compounds of the present invention depends on the inhibition of the F1F0 ATP synthase, in particular the inhibition of the F0 complex of the F1F0 ATP synthase, more specifically the inhibition of the subunit c of the F0 complex of the F1F0 ATP synthase. And depletion of the cellular ATP level of the bacteria induces the death of the bacteria. Thus, in particular, the compounds of the present invention are active against bacteria whose viability depends on the proper action of F1F0 ATP synthase.

Bacterial infections that can be treated by the compounds of the invention include, for example, central nervous system infection, ear canal infection, middle ear infection, such as acute otitis media, cranial sinuses infection, eye infection, oral infection, such as teeth, periodontal and Mucosal infections, Mutual respiratory tract infections, Respiratory tract infections, Urogenital infections, Gastrointestinal infections, Gynecologic infections, Sepsis, Bone and joint infections, Skin and skin structure infections, Bacterial endocarditis, Burns, Surgery, Antibacterial prevention and immunity Prevention of antibacterial in inhibitory patients, such as cancer chemotherapy patients or tracheal transplant patients.

When used above and after, a compound can treat a bacterium, this means that the compound can always treat an infection with one or more bacterial strains.

The present invention relates to a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention as an active ingredient. The compounds of the present invention can be formulated in a variety of pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly used as systemic dosage agents can be cited. To prepare a pharmaceutical composition of the invention, an effective amount of a particular compound in the form of an addition salt, as an active ingredient, is optionally formulated in intimate mixture with a pharmaceutically acceptable carrier, wherein the carrier may vary depending on the form of preparation required for administration. Form). Such pharmaceutical compositions are particularly preferably in single dosage forms suitable for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, in the case of oral liquid preparations such as suspending agents, syrups, elixirs, emulsions and solutions, any conventional pharmaceutical media such as water, glycols, oils, alcohols and the like may be used. Available; In the case of powders, pills, capsules, tablets and the like, solid carriers such as starches, sugars, kaolin, lubricants, binders, and disintegrants may be used. Because of their ease of administration, tablets and capsules represent the most useful oral dosage unit forms, in which case solid pharmaceutical carriers are expressly applied. In the case of parenteral compositions, the carrier generally comprises at least a large proportion in sterile water, although other components may be included, such as to aid dissolution. For example, an injectable solution may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical composition preferably comprises 0.05 to 99% by weight, more preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight of the active ingredient (s), and 1 to 99.95% by weight. More preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of pharmaceutically acceptable carrier, all ratios being relative to the total weight of the composition.

The pharmaceutical composition may further contain various other ingredients known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavors or colorants.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage forms are physically discrete units suited as single dosages, each of which, together with the required pharmaceutical carrier, contains a predetermined amount of active ingredient calculated to provide the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scores or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and their separate multiple batches. The daily dosage of the compounds of the present invention may of course vary depending on the compound used, the mode of administration, the desired treatment and the mycobacterial disease indicated. In general, however, satisfactory results will be obtained if the compound of the invention is administered in a daily dose not exceeding 1 g, for example in the range of 10 to 50 mg / kg body weight.

Given the fact that the compounds of formula (la) or (lb) are active against bacterial infections, the compounds of the present invention may be combined with other antimicrobial agents to effectively control bacterial infections.

Accordingly, the present invention also relates to a combination of (a) a compound of the invention and (b) one or more other antimicrobial agents.

The invention also relates to a combination of (a) a compound of the invention and (b) at least one other antimicrobial agent for use in medicine.

The invention also relates to the use of a combination or pharmaceutical composition as defined above for the treatment of a bacterial infection.

Also provided by the present invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of (a) a compound of the invention and (b) one or more other antimicrobial agents as active ingredients.

When provided in a combination, the weight ratio of (a) the compound of the invention and (b) one or more other antimicrobial agents can be determined by one skilled in the art. This ratio and the exact dosage and frequency of administration, as is well known to those skilled in the art, include the compound of the invention and other antimicrobial agent (s) used, the specific symptoms being treated, and the severity of the treatment, in addition to other medications that can be taken by the individual. Sex, age, weight, sex, diet, time of administration and general physical condition, mode of administration, etc. of a particular patient. It is also evident that the daily effective amount may be lowered or increased depending on the response of the treated individual and / or the assessment of the clinician prescribing the compound of the invention. The specific weight ratios of the compounds of formula (la) or (lb) of the invention and other antimicrobial agents may range from 1/10 to 10/1, in particular from 1/5 to 5/1, especially from 1/3 to 3/1. .

The compounds of the present invention and one or more other antimicrobial agents may be combined in a single formulation or they may be formulated in separate formulations and administered simultaneously, separately or sequentially. Accordingly, the present invention also relates to a product containing (a) a compound of the invention and (b) at least one other antimicrobial agent as a formulated formulation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

Other antimicrobials that can be combined with the compounds of formula (la) or (lb) are antimicrobials known in the art. Other antimicrobial agents include β-lactam antibiotics such as natural penicillin, semisynthetic penicillin, natural cephalosporin, semisynthetic cephalosporin, cephamycin, 1-oxacefem, clavulanic acid, penem, carbapenem, nocardicin, monobactam; Tetracycline, anhydrotetracycline, anthracycline; Aminoglycosides; Nucleosides such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidine S; Macrolides such as 12-membered ring macrolide, 14-membered ring macrolide, 16-membered ring macrolide; Ansamycin; Bleomycin, Gramicidine, Polymyxin, Bacitracin, Cyclopeptide antibiotics containing lactone bonds, Actinomycin, Ampomycin, Capreomycin, Distamycin, Endurasidine, Micamycin, Neocardino Peptides such as statins, standomycin, biomycin, and viremiamycin; Cycloheximide; Ciacloserine; Bariotin; Sarcomycin A; Novobiocin; Griseofulvin; Chloramphenicol; Mitomycin; Fumagillin; Monensin; Pyrronitrin; Fosfomycin; Fusidic acid; D- ( p -hydroxyphenyl) glycine; D-phenylglycine; Contains enedine.

Certain antibiotics that may be combined with the compounds of formula (Ia) or (Ib) of the present invention are, for example, benzylphenicillin (potassium, procaine, benzatin), phenoxymethylphenicillin (potassium), peneticillin potassium, propicillin , Carbenicillin (disodium, phenyl sodium, inmono-sodium), sulfenicillin, ticarcillin disodium, methicillin sodium, oxacillin sodium, clocksacillin sodium, dicloxacillin, flucloxacillin, ampicillin , Mezzocillin, piperacillin sodium, amocillin, cyclacillin, hexillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, fibmesilin, cephalexin, cefachlor, cephaloglycine , Cephadroxyl, cepradine, ceproxadine, cefapirine sodium, cephalotin sodium, cephacetyl sodium, ceftulin sodium, cephaloridine, cephatrizin, cepharazone sodium, cephamandol, bepoti Ammonium hydrochloride, three Pazoline Sodium, Ceftizone Sodium, Cytotaxim Sodium, Cefmenoxime Hydrochloride, Cefuroxime, Ceftriaxone Sodium, Ceftazidime, Sepoxitine, Cefmethazole, Cefetatan, Latamoxef, Clavulanic Acid, Imiphenem, Aztreonam, Tetracycline, Chlortetracycline Hydrochloride, Demethylchlortetracycline, Oxytetracycline, Metacycline, Doxycycline, Lolitetracycline, Minocycline, Daunorubicin Hydrochloride, Doxorubicin, Aklarubicin, Kanamycin Sulphate, becanamycin, tobramycin, gentamycin sulphate, dibecasin, amikacin, micronomycin, ribostamycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dehydrostreptomycin, destomycin A, hydromycin B, apramycin, sisomicin, yes Supersulfate, Spectinomycin Hydrochloride, Astromycin Sulfate, Validamycin, Kasugamycin, Polyoxine, Blastisidine S, Erythromycin, Erythromycin Estoleate, Oleandomycin Phosphate, Tracetyleoleandomycin, Kita Samycin, probemycin, spiramycin, tyrosine, ibemectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidine S, polymyxin B, bacitracin, colistin sulfate, colistin methanesulfonate Sodium, Enlamycin, Mycamycin, Birginiamycin, Capreomycin Sulfate, Biomycin, Enbiomycin, Vancomycin, Actinomycin D, Neocaragenostatin, Vestatin, Pepstatin, Monensin, Lasaloside , Salinomycin, amphotericin B, nystatin, natamycin, trichomycin, mitramycin, lincomycin, clean Damycin, clindamycin palmitate hydrochloride, flabophospholifol, cycloserine, pessilosine, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrronitrine, phosphomycin, Fusidic acid, bicozamycin, thiamulin, cicanin.

Other mycobacterial agents that can be combined with compounds of formula (la) or (lb) include, for example, rifampicin (= rifampin); Isoniazid; Pyrazineamides; Amikacin; Ethionamide; Moxifloxacin; Ethambutol; Streptomycin; Para-aminosalicylic acid; Cycloserine; Capreomycin; Kanamycin; Thioacetazone; PA-824; Quinolones / fluoroquinolones such as moxifloxacin, gatifloxacin, opfloxacin, ciprofloxacin, sparfloxacin; Macrolides such as, for example, clarithromycin, clofazimin, amoxicin (+ clavulanic acid); Rifamycin; Lipabutin; Lipopentin; Compounds disclosed in WO2004 / 011436.

Common manufacturing

The compounds of the present invention may generally be prepared in a series of steps, each known to those skilled in the art.

Compounds represented by formulas (Ia-1) or (Ib-1), wherein R ¹ is a compound of formula (Ia) or (Ib) wherein C _2-6 alkenyl is selected from a suitable catalyst, for example Pd (PPh ₃ ) ₄ In the presence of a suitable solvent, for example N, N-dimethylformamide, in the presence of formula (II-a) or (II-), W ₁ represents a suitable leaving group, for example halo, for example bromo and the like. The intermediate of b) can be prepared by reacting with tributyl (C _2-6 alkenyl) tin, for example tributyl (vinyl) tin. The reaction is preferably performed at high temperature.

Compounds represented by formulas (Ia-2) or (Ib-2) wherein R ¹ is a compound of formula (Ia) or (Ib) representing R ^5a R ^4a N— are suitable catalysts, for example tris (dibenzylideneacetone Palladium, a suitable ligand such as 2- (di-t-butylphosphino) biphenyl, a suitable base such as sodium t-butoxide, and R ^5a R ^{4a in} the presence of a suitable solvent such as toluene By reaction with NH, it may be prepared from an intermediate of formula (II-a) or (II-b).

Compounds represented by formulas (Ia-3) or (Ib-3), wherein R ¹ is a compound of formula (Ia) or (Ib) wherein -C = N-OR ¹¹ are hydrated in the presence of a suitable solvent, for example pyridine. hydroxylamine hydrochloride or C _{1 - 6} alkoxyl, by reaction of the amine hydrochloride, can be prepared from intermediates of formula (III-a) or (III-b).

The compound represented by formula (Ia-4) or (Ib-4), wherein R ¹ is a compound of formula (Ia) or (Ib) representing -CH ₂ -NH ₂ , is supported on H ₂ , a suitable catalyst, for example activated carbon. Prepared palladium and intermediates of formula (III-a) or (III-b) by reduction in the presence of a suitable solvent such as NH ₃ / alcohol such as NH ₃ / methanol.

Compounds represented by formulas (Ia-5) or (Ib-5) wherein R ¹ is a compound of formula (Ia) or (Ib) representing R ^5a R ^4a N—CH ₂ — are suitable reducing agents, for example BH ₃ CN In the presence of a suitable solvent such as acetonitrile and tetrahydrofuran, and a suitable acid such as acetic acid, the intermediate of formula (III-a) or (III-b) with a suitable reagent of formula R ^5a R ^4a NH It can be prepared by reacting.

Compounds represented by formulas (Ia-6) or (Ib-6), wherein R ¹ is a compound of formula (Ia) or (Ib) which represents amino, are formula (IV-a) or (IV) in a suitable solvent such as toluene. The intermediate of -b) can be prepared by reacting with a suitable azide, for example diphenylphosphoryl azide (DPPA), and a suitable base, for example triethylamine. The product obtained undergoes a modified Curtius reaction and trimethylsilylethanol is added to produce a carbamate intermediate. In the next step, this intermediate is reacted with tetrabutylammonium bromide (TBAB) in a suitable solvent such as tetrahydrofuran to give an amino derivative.

R ¹ is aminocarbonyl, mono- or di (alkyl) aminocarbonyl or ^{R 5a R 4a NC (= O} ) - is represented by the compound of R ¹ is R ^1a in the general formula (Ia) or (Ib) represents the formula Compounds represented by (Ia-7) or (Ib-7) may be prepared by the intermediate of formula (IV-a) or (IV-b) with an appropriate amine, a suitable coupling reagent such as hydroxybenzotriazole, a suitable activator. Suitable carbodiimides such as 1,1'-carbonyldiimidazole or N, N'-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, suitable It can be prepared by reacting with a base such as triethylamine and a suitable solvent such as tetrahydrofuran and methylene chloride.

Compound represented by formula (Ia-8) or (Ib-8), wherein R ¹ is a compound of formula (Ia) or (Ib) representing arylcarbonyl, comprises n-BuLi and a suitable solvent in the first step (a), eg For example, it may be prepared by reacting an intermediate of formula (II-a) or (II-b) with a suitable arylaldehyde in the presence of tetrahydrofuran. This reaction is preferably carried out at low temperature, for example -70 ° C. In the next step (b), the product obtained in step (a) is oxidized with a suitable oxidizing agent, for example manganese oxide, in the presence of a suitable solvent, for example methylene chloride.

Compounds of formula (la) or (lb) may be formulated using n-BuLi in a mixture of a suitable base such as diisopropyl amine with a suitable solvent such as tetrahydrofuran according to the following scheme. It may be prepared by reacting an intermediate of (Va) or (Vb) with an intermediate of formula (VI):

Wherein all variables are as defined in formula (la) or (lb)).

Agitation can improve the reaction rate. The reaction may conveniently be carried out at a temperature of -20 to -70 ° C.

Compounds represented by formulas (Ia-9) or (Ib-9), which are compounds of formula (Ia) or (Ib) wherein q is 2, 3 or 4, are suitable catalysts at elevated temperatures, for example Rh (cod) ₂ BF _In the presence of ₄ , optionally in the presence of a second catalyst (for reducing), for example Ir (cod) ₂ BF _{4, in} the presence of a suitable ligand, for example Xantphos, a suitable solvent, for example tetrahydro. Intermediates of the formula (VII-a) or (VII-b) with q '0, 1 or 2 in the presence of CO and H ₂ (under pressure) in furan and alcohols, for example methanol, are primary or secondary amines. It can be prepared by reacting with HNR ⁴ R ⁵ . This reaction is preferably carried out on intermediates of formula (VII) wherein q 'is 1.

The compounds of formula (la) or (lb) may also optionally contain a compound of formula (W) in which W ₂ represents a suitable leaving group such as halo, for example chloro or bromo, optionally in the presence of a suitable solvent such as acetonitrile It can be prepared by reacting the intermediate of VIII-a) or (VIII-b) with the primary or secondary amine HNR ⁴ R ⁵ .

It is within the knowledge of those skilled in the art to investigate the appropriate temperature, dilution and reaction time to optimize the reaction to obtain the desired compound.

Compounds of formula (la) or (lb) can also be prepared by converting compounds of formula (la) or (lb) to one another according to transformation reaction groups known in the art.

Compounds of formula (la) or (lb) can be converted to the corresponding N-oxide form according to procedures known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can usually be carried out by reacting the starting material of formula (la) or (lb) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; Suitable organic peroxides are peroxy acids, for example benzene carboperoxo acid or benzene carboperoxo acids substituted with halo, for example 3-chlorobenzenecarboperoxo acid, peroxoalkanoic acid, for example per Oxoacetic acid, alkylhydroperoxides, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and these There is a mixture of solvents.

Compounds of formula (la) or (lb) are suitable quaternizing agents, for example, optionally substituted C _1-6 alkyl halides, aryl C _1-6 alkyl halides, C _{1 in} the presence of a suitable solvent such as acetone. Can be converted to quaternary amines by reaction with _-6 alkylcarbonyl halides, arylcarbonyl halides, Het ¹ C _1-6 alkyl halides or Het ¹ carbonyl halides, for example methyl iodide or benzyl iodide, Wherein Het ¹ is furanyl or thienyl; Or a bicyclic heterocycle selected from benzofuranyl or benzothienyl; Each monocyclic and bicyclic heterocycle may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C _1-6 alkyl and aryl, respectively. Wherein the quaternary amine R ¹⁰ represents C _1-6 alkyl, C _1-6 alkylcarbonyl, arylC _1-6 alkyl, arylcarbonyl, Het ¹ C _1-6 alkyl or Het ¹ carbonyl, and A ⁻ is Represented by the following formulae representing a pharmaceutically acceptable counterion, for example iodide.

Compounds of formula (la) or (lb) in which R ⁶ represents phenyl substituted with halo may be selected from a suitable base such as Na ₂ CO ₃ , and in the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ . Phenyl in which R ⁶ is substituted by Het by reaction with Het-B (OH) ₂ in the presence of a suitable solvent such as toluene or 1,2-dimethoxyethane (DME) and an alcohol such as methanol It can be converted to a compound of formula (la) or (lb) represented.

Compounds of formula (Ia-4) or (Ib-4) are reacted with appropriate alkylcarbonyl chlorides in the presence of a suitable base such as N, N-diethylethanamine and a suitable solvent such as methylene chloride By R ¹ can be converted to a compound of formula (la) or (lb) which represents alkylcarbonylamino-CH _2- .

The compound of formula (Ia-4) or (Ib-4) may be reacted with a suitable aldehyde or ketone reagent such as paraformaldehyde or formaldehyde in the presence of sodium cyanoborohydride, acetic acid and a suitable solvent such as acetonitrile. By reaction of R ¹ can be converted to a compound of formula (la) or (lb) which represents -CH ₂ -N (C _1-6 alkyl) ₂ .

Compounds of formula (Ia) in which R ² represents methoxy are hydrolyzed in the presence of a suitable acid such as hydrochloric acid and a suitable solvent such as dioxane, where R ⁸ is hydrogen, and R ⁹ is Oxo which can be converted to the corresponding compound of formula (lb).

In the above-described reactions and the following reactions, it is apparent that the reaction product can be separated from the reaction medium and, if necessary, further purified by methods commonly known in the art, such as extraction, crystallization and chromatography. Do. The reaction products present as one or more ethanethiomers can be separated from their mixtures by known techniques, in particular preparative chromatography such as preparative HPLC, chiral chromatography. Each diastereo isomer or each enantiomer may also be obtained by supercritical fluid chromatography (SCF).

Starting materials and intermediates are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formulas (IIa) to (IId) can be prepared according to the methods described in WO2004 / 011436, WO2005 / 070924, WO2005 / 070430 or WO2005 / 075428, the contents of which are incorporated herein by reference.

In particular, intermediates of the formula (II-a) or (II-b) are, according to Scheme 1, n- in a mixture of a suitable base such as diisopropyl amine and a suitable solvent such as tetrahydrofuran. Using BuLi, it may be prepared by reacting an intermediate of formula (IX-a) or (IX-b) with an intermediate of formula (VI):

Scheme 1

Wherein all variables are as defined in formula (la) or (lb)).

Agitation can improve the reaction rate. The reaction may conveniently be carried out at a temperature of -20 to -70 ° C.

The intermediate of formula (III-a) or (III-b) is reacted with N, N-dimethylformamide in the presence of a suitable solvent, for example tetrahydrofuran, to formula (Il-a) or (II- from the intermediate of b). The reaction is preferably carried out at low temperature, for example -70 ° C.

Intermediates of formula (IV-a) or (IV-b) may be prepared by reacting with CO ₂ in the presence of n-BuLi and a suitable solvent, for example tetrahydrofuran. It can be prepared from an intermediate. The reaction is preferably carried out at low temperature, for example -70 ° C.

Intermediates of formula (V-a) can be prepared according to Scheme 2:

Scheme 2

Wherein all variables are as defined in formula (la). Scheme 2 provides a suitable acylchloride such as 3-phenylpropionyl chloride, 3- in the presence of a suitable substituted aniline in a suitable base such as triethylamine, and a suitable reaction inert solvent such as methylene chloride or ethylene dichloride. Reacting with fluorobenzenepropionyl chloride or p-chlorobenzenepropionyl chloride (a). The reaction may conveniently be carried out at a temperature in the range from room temperature to reflux temperature. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl ₃ ) in the presence of N, N-dimethylformamide (Vilsmeier-Haack formylation followed by , Cyclization). The reaction may conveniently be carried out at a temperature in the range from room temperature to reflux temperature. In a next step (c-1), a specific R ² group (wherein, R ² is, for example, C _{1 - 6} alkyl-oxy radical) is an appropriate solvent, e.g., HO-C _{1 -} in the presence of ₆ alkyl , the intermediate compound obtained in step (b) ^- is introduced by reaction with _{6-alkyl -} OC _1. The intermediate obtained in step (b) may also contain S = C (NH) in the presence of a suitable solvent such as an alcohol such as ethanol, or an alcohol / water mixture, optionally in the presence of a suitable base such as KOH. ₂ ) reaction with ₂ (see step (c-2)), followed by C _1-6 alkyl-I in the presence of a suitable base such as K ₂ CO ₃ and a suitable solvent such as 2-propanone By reaction with (see step (d)), R ² can be converted to an intermediate, for example C _1-6 alkylthio radicals. The intermediate obtained in step (b) may also be reacted with a suitable salt of NH (R ^2a ) (alkyl) in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile (step (c -3)) can be converted to an intermediate in which R ² is -N (R ^2a ) (alkyl), wherein R ^2a is hydrogen or alkyl. Intermediates obtained in step (b) is also NaH and a suitable solvent, for example, in the presence of tetrahydrofuran, C _{1 - 6,} optionally substituted by alkyloxy C _{1 - 6} alkyloxy C _{1 -} reaction (step with ₆ alkyl OH (c-4)) to, R is a ^divalent optionally substituted C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyloxy as a result, can R ² can be converted to intermediates represented by R ^2b.

Intermediates represented by formula (Va-5), wherein R ² and R ⁷ are intermediates of formula (Va) representing hydrogen, can be prepared according to Scheme 3 below, wherein indole-2 substituted in the first step (a), 3-dione is reacted with 3-phenylpropionaldehyde optionally substituted in the presence of a suitable base such as sodium hydroxide (Pfitzinger reaction), and the carboxylic acid compound is then subjected to the next step at high temperature in the presence of a suitable reaction inert solvent such as diphenylether decarboxylated in (b).

Scheme 3

Intermediates represented by formula (Va-6), wherein R ⁶ is an intermediate of formula (Va) representing Het, can be prepared according to Scheme 3a.

Scheme 3a

Scheme 3a uses n-BuLi in an appropriate quinoline moiety in a mixture of a suitable base such as 2,2,6,6-tetramethylpiperidine and a suitable solvent such as tetrahydrofuran, Reacting with Het-C (= 0) -H, comprising the step (a). Agitation can improve the reaction rate. The reaction may conveniently be carried out at a temperature of -20 to -70 ° C. In the next step (b), the product obtained in step (a) is reacted with a suitable acid, for example trifluoroacetic acid, and triisopropylsilane in the presence of a suitable solvent, for example methylene chloride, Converted to the intermediate of formula (Va-6).

Intermediates of formula (V-b), in particular (V-b-1) or (V-b-2), can be prepared according to Scheme 4 below.

Scheme 4

Scheme 4 includes the step (a) in which the quinoline moiety is converted to the quinolinone moiety by reaction with a suitable acid, for example hydrochloric acid. In the next step (b), the R ⁸ substituent is added to the appropriate alkylating agent in the presence of a suitable base such as NaOH or benzyltriethylammonium chloride, a suitable solvent such as tetrahydrofuran For example, it is introduced by reacting with alkyl iodide, for example methyl iodide.

Intermediates represented by formula (Vb-3), wherein R ⁸ and R ⁹ together form a radical -CH = CH-N =, can be prepared according to Scheme 5 below.

Scheme 5

Scheme 5 includes step (a) in which the intermediate reacts with NH ₂ —CH ₂ —CH (OCH ₃ ) ₂ . In the next step (b), the fused imidazolyl moiety is formed by reaction with acetic acid in the presence of a suitable solvent, for example xylene.

Intermediates of formula (VI) are commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (VI) can be prepared according to Scheme 6:

Scheme 6

Scheme 6 shows that R ³ , in particular suitably substituted aryl, in particular suitably substituted phenyl, is a suitable Lewis acid such as AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl ₂ and a suitable reaction inert solvent such as methylene chloride Or reacting by a Friedel-Craft reaction with a suitable acylchloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride in the presence of ethylene dichloride. The reaction may conveniently be carried out at a temperature in the range from room temperature to reflux temperature. In the next step (b), the amino group (-NR ⁴ R ⁵ ) is introduced by reacting the intermediate obtained in step (a) with the primary or secondary amine (HNR ⁴ R ⁵ ).

Intermediates of formula (VI) can also be prepared according to Scheme 7:

Scheme 7

Scheme 7 shows R ³ -C (═O) -H, for example, a suitably substituted arylcarboxaldehyde, in particular a suitably substituted phenyl or naphthylcarboxaldehyde with Grignard reagents and a suitable solvent, for example diethyl. Reacting with a suitable intermediate compound, such as 1-bromo-4-chlorobutane, in the presence of an ether, tetrahydrofuran. The reaction may conveniently be carried out at low temperature, for example 5 ° C. In the next step (b), the oxidation is carried out in a suitable solvent, for example acetone, in the presence of Jones reagent. In the next step (c), the amino group (-NR ⁴ R ⁵ ) is prepared from the intermediate compound obtained in step (b) in the presence of a suitable solvent such as acetonitrile and a suitable base such as K ₂ CO ₃ . It is introduced by reacting with primary or secondary amines (HNR ⁴ R ⁵ ).

Alternatively, intermediates of formula (VI) can be prepared according to Scheme 8:

Scheme 8

Scheme 8 includes, for example, reacting a suitable acid with NH (CH ₃ ) (OCH ₃ ) in the presence of 1,1′-carbonyldiimidazole and a suitable solvent such as CH ₂ Cl ₂ (a) It includes. In the next step (b) the product obtained in step (a) is reacted with a suitable Grignard reagent such as 4-chlorobutyl magnesium bromide in the presence of a suitable solvent such as tetrahydrofuran. In the next step (c), the amino group (-NR ⁴ R ⁵ ) is the primary product of the intermediate obtained in step (b) in the presence of a suitable solvent such as acetonitrile and a suitable base such as K ₂ CO ₃ . Or by reacting with a secondary amine (HNR ⁴ R ⁵ ).

Alternatively, the intermediate represented by formula (VI-a), which is an intermediate of formula (VI) wherein q is 1, can be prepared according to Scheme 9:

Scheme 9

Scheme 9 shows that a suitable acetyl derivative of R ³ , for example acetylcyclohexane, is paraformaldehyde in the presence of a suitable acid such as hydrochloric acid, and a suitable solvent such as alcohol, such as ethanol. And preferably reacting with a suitable primary or secondary amine HNR ⁴ R ^{5 in} salt form thereof.

R ³ is R ^{3a '} -CH ₂ -CH _2- (R ³ is alkyl, arylalkyl, aryl-O-alkyl, aryl-alkyl-O-alkyl, Het-alkyl, Het-O-alkyl or Het-alkyl- Possible for intermediates of formula (VI) representing O-alkyl), wherein R ^{3a ′} is the same as R ³ , but the alkyl chain bonded to the rest of the molecule has less than 2 carbon atoms and q represents 1 Intermediates represented by formula (VI-b), which are intermediates of (VI), can be prepared according to Scheme 10 below:

Scheme 10

Scheme 10 includes the step (a) of reacting a suitable aldehyde with acetone in the presence of a suitable base such as sodium hydroxide. In the next step (b), the product obtained in step (a) is prepared in the presence of CH ₂ (═O), a suitable acid such as hydrochloric acid and the like, and a suitable solvent such as alcohol such as ethanol React with primary or secondary amine HNR ⁴ R ⁵ . In the next step (c), the product obtained in step (b) is hydrogenated in the presence of a suitable catalyst such as palladium supported on activated carbon and a suitable solvent such as water and alcohols such as ethanol (H ₂ ).

Intermediates of formula (VII-a) can be prepared according to Scheme 11 below:

Scheme 11

Scheme 11 shows the presence of a suitable catalyst such as palladium diacetate, a suitable ligand such as X-PHOS, a suitable base such as cesium carbonate, a suitable solvent such as xylenes under N ₂ air flow. Under reaction, a suitably substituted quinoline in which W ₂ represents a suitable leaving group such as halo, eg bromo, is reacted with a suitably substituted deoxybenzoin. In the next step (b), the product obtained in step (a) is subjected to a suitable Grignard reagent (e.g. CH ₂ = CH- (CH ₂ ) _q -Mg-Br, in a suitable solvent such as tetrahydrofuran, For example, allyl magnesium bromide). Thus, intermediates of formula (VII-b) can be prepared.

Intermediates of formula (VIII-a) can be prepared according to Scheme 12:

Scheme 12

In Scheme 12, the intermediate of formula (Va) is in the presence of n-BuLi in a suitable solvent, for example tetrahydrofuran, and a suitable base, for example diisopropyl amine, for the synthesis thereof. With reference to 6, 7 and 8, it reacts with the intermediate of formula (X). Agitation can improve the reaction rate. The reaction may conveniently be carried out at a temperature in the range of -20 to -70 ° C. Thus, intermediates of formula (VIII-b) can be prepared.

Intermediates of formula (IX-a) or (IX-b) may be prepared according to the reaction procedures described above for intermediates (V-a) or (V-b).

The following examples illustrate the invention without being limited thereto.

Experimental part

Among some of the compounds or intermediates, no absolute stereochemical configuration of the stereogenic carbon atom (s) or the configuration at the double bond in this specification has been determined experimentally. Also, regardless of the actual stereochemical configuration, the first separated stereochemical isomer is denoted by "A" and the second separated by "B". However, the "A" and "B" isomers can be clearly characterized by multiple practitioners using methods known in the art, such as NMR. It is contemplated to be within the knowledge of those skilled in the art to recognize the most appropriate way to determine the actual stereochemical configuration.

When "A" and "B" are stereoisomeric mixtures, especially mixtures of enantiomers, they can be separated, so that each separated first fraction is each of "A1" and "regardless of the actual stereochemical configuration. B1 ", and the second fraction is represented as" A2 "and" B2 ", respectively. However, the "A1", "A2" and "B1", "B2" isomers, in particular the "A1", "A2" and "B1", "B2" enantiomers are known in the art, for example X-ray diffraction can be used to clearly characterize those skilled in the art.

In some cases, when the final compound or intermediate represented as a particular diastereoisomer or enantiomer is converted to another final compound / intermediate, the latter is the diastereoisomer (A, B) or enantiomer (A1, The indications for A2, B1, and B2) can be taken over.

Hereinafter, "DMF" means N, N-dimethylformamide, "iPA" means isopropylamine, "THF" means tetrahydrofuran, and "DIPE" means diisopropyl ether. .

A. Preparation of Intermediate Compounds

Example A1

a. Preparation of Intermediate 18a

A mixture of 4- (4-fluorophenyl) -2-butanone (0.029 mol), formaldehyde (0.116 mol) and N-methylmethanamine (0.116 mol) in concentrated HCl (1.4 ml) and ethanol (48 ml) The mixture was stirred and refluxed for 24 hours and then allowed to come to room temperature. HCl 1 N was added. The mixture was washed with diethyl ether, basified with K ₂ CO ₃ 2 M and extracted with diethyl ether. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 95/5 / 0.1; 15-40 μm). Two fractions were combined and the solvent was evaporated. Yield: 1.6 g of intermediate 18a (49%).

b. Preparation of Intermediate 1

N-BuLi 1.6 M (0.0056 mol) in hexane was added dropwise to a solution of N- (1-methylethyl) -2-propanamine (0.0564 mol) in THF (10 ml) at -20 ° C under N ₂ stream. The mixture was stirred at -20 ° C for 20 minutes and then cooled to -70 ° C. A solution of 6-bromo-2-methoxy-3- (phenylmethyl) -quinoline [654655-69-3] (intermediate compound 3 of WO 2004/011436) (0.0051 mol) in THF (20 ml) was added. . The mixture was stirred at -70 ° C for 90 minutes. Intermediate 18a (prepared according to A1.a) (0.0072 mol) in THF (18 ml) was added solution. The mixture was stirred at -70 ° C for 3 hours. H ₂ O was added at -30 ° C. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98.5 / 1.5 / 0.1; 15-40 μm), followed by chromamar (eluent: CH ₂ Cl ₂ / CH ₃ OH). / NH ₄ OH 99/1 / 0.1; 100 μm) was purified by column chromatography. Two fractions were combined and the solvent was evaporated. Yield: 0.2 g of fraction 1 and 0.13 g of fraction 2. Two fractions were crystallized with DIPE. The precipitate was filtered off and dried. Yield: 0.146 g of intermediate 1 (5%) (mp 148 ° C.) and 0.076 g of intermediate 2 (3%) (mp 157 ° C.).

c. Preparation of Intermediates 14 and 15

N-BuLi 1.6 M (0.0018 mol) in hexane was added dropwise to a solution of diisopropylamine (0.0018 mol) in THF (4 ml) at -20 ° C. under N ₂ stream. The mixture was stirred at -20 ° C for 20 minutes and then cooled to -70 ° C. 6-bromo-2-methoxy-3- (phenylmethyl) -quinoline described in WO2004 / 011436, the contents of which are incorporated herein by reference, as intermediate 3 in THF (5 ml) [654655-69-3] (0.0015 mol) of solution was added. The mixture was stirred at -70 ° C for 90 minutes. A solution of 1-phenyl-5- (1-piperidinyl) -1-pentanone (0.0018 mol) in THF (5 ml) was added. The mixture was stirred at -70 ° C for 90 minutes. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.9 g) was purified by column chromatography on chromamar (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97/3 / 0.1; 10 μm). Two fractions were combined and the solvent was evaporated. Yield: 0.085 g of Intermediate 14 (10%; mp 129 ° C.) and 0.133 g of second fraction (15%). This fraction was crystallized with DIPE. The precipitate was filtered off and dried at 60 ° C. under vacuum. Yield: 0.05 g of intermediate 15 (6%; mp 166 ° C.).

Example A2

a-1. Preparation of Intermediate 4

N-BuLi 1.6 M (0.0071 mol) in hexane was added dropwise to a solution of 25903852 compound 190 (0.0028 mol) of WO2004 / 011436 in THF (17 ml) at -70 ° C. under N ₂ stream. The mixture was stirred at -70 ° C for 1 hour. A solution of N, N-dimethylformamide (0.014 mol) in THF (11 ml) was added at -70 ° C. The mixture was stirred at -70 ° C for 2 hours. The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. Yield: 1.45 g of intermediate 4 (diastereo isomer A).

Intermediate 5 was prepared following the same procedure as intermediate 4, but using compound 191 of WO2004 / 011436 as a starting material. Yield: 0.92 g of intermediate 5 (diastereo isomer B).

a-2. Preparation of Intermediate 3

Following the same procedure as Intermediate 4, Intermediate 3 was prepared using Compound 66 of WO 2004/011436 as starting material. The residue was crystallized with DIPE. Yield: 0.60 g of intermediate 3 (69%; diastereo isomer B).

a-3. Preparation of Intermediates 10, 11, 12 and 13

N-BuLi (1.6 M in hexanes, 14.1 ml, 0.0225 mol) was added dropwise to a solution of compound 14 (5.O g, 9.0 mmol) of WO2004 / 011436 in THF (50 ml) at -70 ° C. under a nitrogen stream. The mixture was stirred at −70 ° C. for 90 minutes, then N, N-dimethylformamide (5.5 ml, 0.072 mol) was added. The resulting mixture was stirred at −70 ° C. for 2 hours and then water was added. The mixture was extracted with EtOAc. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was crystallized from diisopropyl ether and methanol. Yield: 1.7 g of intermediate 10 (38%).

Intermediate 11 (diastereoisomer B) was prepared according to intermediate 10 but using compound 15 (B) of WO2004 / 011436 as starting material. Yield: 1.0 g of intermediate 11 (22%).

According to Intermediate 10, Intermediate 12 (A1; 1R, 2S) was prepared using Compound 12 (A1; 1R, 2S) of WO2004 / 011436 as starting material. Yield: 3.8 g of intermediate 12.

According to Intermediate 10, Intermediate 13 (A2; 1S, 2R) was prepared using Compound 13 (A2; 1S, 2R) of WO2004 / 011436 as a starting material. Yield: 2 g of intermediate 13.

Example A3

Preparation of Intermediate 6

6-Bromo-2-methoxy-3- (phenylmethyl) -quinoline [654655-69-3] (2.0 g, 6.1 mmol), mor, described as intermediate compound 3 in WO2004 / 011436 in toluene (20 ml) Pauline (0.644 ml, 7.3 mmol), Tris (dibenzylideneacetone) palladium (0.28 g, 0.31 mmol), 2- (di-t-butylphosphino) biphenyl (0.18 g, 0.61 mmol) and sodium tert-butoxide The solution of the side (0.82 g, 8.54 mmol) was stirred at 80 ° C. for 24 h, then cooled to rt and poured into water. The organic layer was extracted with EtOAc, washed with water and brine, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40 μm, 20Og, cyclohexane / EtOAc 80:20). Fractions were combined and the solvent was evaporated. Yield: 2.4 g of Intermediate 6 (Yield: 78%).

Example A4

a. Preparation of Intermediate 7

N-BuLi (1.6 M in hexanes, 14.1 ml, 0.0225 mol) was added dropwise to a solution of compound 14 (5.0 g, 9.0 mmol) of WO2004 / 011436 in THF (50 ml) at -70 ° C. under a nitrogen stream. The mixture was stirred at -70 [deg.] C. for 2 hours and then dry ice was added. The resulting mixture was stirred at −70 ° C. for 1 hour and then water was added. The precipitate was filtered off, washed with water, CH ₃ OH, then CH ₃ CH ₂ OH, and dried under vacuum. Yield: 0.8 g of intermediate 7 (17%). A second fraction was obtained from the filtrate. Yield: 1.3 g of intermediate 7 (28%).

b. Preparation of Intermediates 8 and 9

Diphenylphosphoryl azide (DPPA, 0.454 ml, 2.11 mmol) under nitrogen stream was added to intermediate 7 (prepared according to A4.a) (1.1 g, 2.11 mmol) and triethylamine (0.297 ml) in toluene (20 ml). , 2.11 mmol). The mixture was stirred at 80 ° C. for 2 hours, then 2- (trimethylsilyl) ethanol (0.61 ml, 4.2 mmol) was added. The solution was stirred at 80 ° C. for 5 hours and then at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (1.3 g) was purified by column chromatography on silica gel (SiO ₂ 15-40 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 98/2 / 0.1). Pure fractions were combined and the solvent was evaporated. Yield: 0.46 g of intermediate 8 (34%).

Following the same procedure as intermediate 8 (diastereo isomer A), intermediate 9 (diastereo isomer B) was prepared using compound 15 of WO 2004/011436 as starting material. Yield: 0.70 g of intermediate 9 (52%).

Example A5

a. Preparation of Intermediates 16 and 17

N-BuLi 1.6 M (0.563 ml, 0.90 mmol) in hexane was added dropwise to a solution of compound 12 (0.25 g, 0.45 mmol) of WO2004 / 011436 in THF (3 ml) cooled at −70 ° C. under N ₂ atmosphere. The mixture was stirred at −70 ° C. for 1 hour, then a solution of 3-bromobenzaldehyde (0.105 ml, 0.90 mmol) in THF (0.5 ml) was added slowly. The reaction mixture was stirred for 1 hour at -70 ° C and then diluted with water at -40 ° C. The organic layer was extracted with ethyl acetate and washed with brine. The organic layer was then dried (MgSO ₄ ), filtered and concentrated. The crude product (0.34 g) was purified by chromatography on silica gel (15-40 μm, 30 g, CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97: 3: 0.1). Yield: 0.11 g of Intermediate 16 (37%; 1R, 2S).

Following the same procedure as Intermediate 16, Intermediate 17 (diastereoisomer A) was prepared using compound 14 of WO2004 / 011436 as starting material. Yield: 0.11 g of intermediate 17 (34%).

b. Preparation of Intermediate 18

Thus, intermediate 18 (diastereoisomer B) was prepared following the same procedure as intermediate 16 but using compound 36 of WO2004 / 011436 as a starting material. Yield: 0.13 g of intermediate 18 (36%).

B. Preparation of Final Compound

Example B1

a. Preparation of Compounds 8, 9 and 10

Compound 14 of WO 2004/011436 in N, N-dimethylformamide (3 ml) (diastereoisomer A, mixture of RS and SR) (0.1 g, 0.18 mmol), tributylvinyltin (0.114 g, 0.36 mmol) And a mixture of PdCl ₂ (PPh ₃ ) ₂ (0.013 g, 0.018 mmol) was heated at microwave (80 ° C., 10 min, 100 W). The mixture was cooled, poured into an aqueous KF solution (10% w / w), extracted with EtOAc and filtered through a short pad of celite. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (0.26 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ : 100 to CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH; 98/2 / 0.2). Pure fractions were combined and the solvent was evaporated. Yield: 0.018 g of compound 8 (diastereo isomer A; yield: 45%, mp: 164 ° C.).

Following the same procedure, compound 9 was prepared using compound 12 (αS, βR; [843663-66-1]) of WO 2004/011436 as starting material. Yield: 0.060 g of compound 9 (A1; 1R, 2S; yield: 45%).

Following the same procedure, compound 10 was prepared using starting compound 15 (a mixture of diastereo isomers B, RR and SS) of WO 2004/011436. Yield: 0.055 g of Compound 10 (diastereo isomer B; yield: 31%, mp: 185 ° C.).

b. Preparation of Compounds 13 and 14

Compound 13 was prepared following the procedure for compound 8 but using the appropriate alkyne reagent. Yield: 45% (diastereo isomer A; mp: 100 ° C.)

Compound 14 was prepared following the procedure for compound 10, but using the appropriate alkyne reagent. Yield: 51% (diastereo isomer B; mp: 202 ° C.).

c. Preparation of Compounds 1 and 2

Compound 1 was prepared according to the procedure for compound 8 but using compound 37 (diastereo isomer A) of WO 2004/011436 as a starting material. Yield: 25% (diastereo isomer A; m. P .: 184 ° C.).

Compound 2 was prepared according to the procedure for compound 10 but using compound 36 (diastereo isomer B) of WO 2004/011436 as a starting material. Yield: 23% (diastereo isomer B; m. P .: 187 ° C.).

d. Preparation of Compounds 11 and 12

Compound 11 was prepared following the procedure for compound 8. Yield: 65% (diastereo isomer A, (E); mp: 190 ° C .;)

Compound 12 was prepared following the procedure for compound 10. Yield: 47% (diastereo isomer B, (E): mp: 189 ° C.).

e. Preparation of Compounds 6 and 7

A solution of intermediate 1 (0.2 g, 0.00036 mol), tributyl (vinyl) tin (0.21 ml, 0.000725 mol) and dichlorobis (triphenylphosphine) palladium (0.025 g, 0.000036 mol) in DMF (4 ml) Stir for 10 minutes at 80 ° C. in wave (100 W). Then extra tributyl (vinyl) tin (1 equiv) and dichlorobis (triphenylphosphine) palladium (0.05 equiv) were added and the mixture was stirred again at 80 ° C. for 10 min in microwave (100 W). . The mixture was then cooled to rt, poured into KF 10% solution and diluted with EtOAc. The mixture was stirred at rt for 1 h, filtered through celite and washed with water. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH; 100/0/0 to 97/3 / 0.3; Sunfire 5 μm). Pure fractions were combined and the solvent was evaporated. The product was then crystallized with DIPE. Yield: 0.067 g of compound 6 (37%; mp: 135 ° C.).

Thus, following the same procedure, compound 7 was prepared using Intermediate 2 (prepared according to A1.b) as starting material. Yield: compound 7 (20%; m p: 156 ° C).

f. Preparation of Compounds 34 and 35

Of intermediate 14 (prepared according to A1.c (0.35 mmol), tributyl (vinyl) tin (0.7 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.035 mmol) in N, N-methylformamide (4 ml) The mixture was heated under microwave (80 ° C., 30 ′, 100 W) The mixture was cooled and poured into an aqueous KF solution (10% w / w) EtOAc was added and the mixture was filtered through a short pad of celite. The filtrate was decanted and the organic layer was washed with water then brine, dried over MgSO ₄ , filtered and evaporated to dryness The residue was SFC (pyridine column, eluent: CO ₂ / MeOH / isopropyl). Amine: 80/20 / 0.5) Pure fractions were collected and solvent was evaporated Yield: 0.02 g of compound 34 (diastereo isomer A; 11%).

Compound 35 was prepared following the procedure for compound 34, but using Intermediate 15 (prepared according to A1.c) as a starting material. Yield: 0.045 g of compound 35 (diastereo isomer B) (25%).

Example B2

a. Preparation of Compounds 32 and 33

A solution of intermediate 4 (prepared according to A2.a-1) (0.38 mmol) and hydroxylamine hydrochloride (0.57 mmol) in pyridine (2 ml) was stirred at rt for 18 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue (0.4 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 96/4 / 0.4 to 88/12 / 1.2; Chromasil Si 5 μm). Pure fractions were combined and the solvent was evaporated. Yield: 0.044 g of compound 33 (21%, mpl 80 ° C).

Following the same procedure, Compound 32 was prepared using Intermediate 5 (prepared according to A2.a-1) as starting material. Yield: 0.1 g of compound 32 (diastereo isomer B) 33%.

b. Preparation of Compound 3

Compound 3 was prepared according to the procedure for compound 33, but using intermediate 3 (prepared according to A2.a-2) as a starting material. Yield: 0.072 g of compound 3 (diastereo isomer B) 43%.

c. Preparation of Compound 4

Compound 4 was prepared following the procedure for compound 33 but using Intermediate 3 (prepared according to A2.a-1) and methoxylamine hydrochloride as starting materials. Yield: 0.082 g of compound 4 (diastereo isomer B) 48%.

d. Preparation of Compounds 23 and 24

A mixture of intermediate 10 (diastereo isomer A) (prepared according to A2.a-3) (0.15 g, 0.297 mmol) and hydroxylamine hydrochloride (0.031 g, 0.446 mmol) in pyridine (2 ml) at room temperature Stir overnight, pour into water and extract with EtOAc. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (0.17 g) was purified by silica gel (Sunfire 5 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 99/1 / 0.1 to CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 94 /6/0.5) on column chromatography. Pure fractions were combined and the solvent was evaporated. Yield: 0.07 g of compound 23 (46%, mp = 187 ° C).

Following the same procedure as compound 23, compound 24 (diastereo isomer B) was prepared starting with intermediate 11 (diastereo isomer B) (prepared according to A2.a-3). Yield: 0.064 g of Compound 24 (41%, m.p. 167 ° C).

e. Preparation of Compounds 25 and 26

Compound 26 was prepared according to the procedure for compound 23 but using Intermediate 10 (prepared according to A2.a-3) and methoxylamine hydrochloride as starting materials. Yield: 0.083 g of compound 26 (diastereo isomer A) (39%; m.p. = 170 ° C).

Compound 25 was prepared according to the procedure for compound 23 but using Intermediate 11 (prepared according to A2.a-3) and methoxylamine hydrochloride as starting materials. Yield: 0.115 g of compound 25 (diastereo isomer B) (54%; m.p. = 228 ° C).

Example B3

a. Compound 5 and 36

N-BuLi 1.6 M (2.24 ml, 3.60 mmol) in hexane was added slowly to a solution of diisopropylamine (0.503 ml, 3.60 mmol) in THF (8 ml) at -20 ° C. under N ₂ stream. The mixture was stirred at -20 ° C for 20 minutes and then cooled at -70 ° C. A solution of intermediate 6 (prepared according to A3) (1.0 g, 3.0 mmol) in THF (10 ml) was added slowly. The mixture was stirred at -70 ° C for 3 hours. A solution of 3- (dimethylamino) -1-phenyl-1-propanone (0.64 g, 3.6 mmol) in THF (7 ml) was added slowly. The mixture was stirred at −70 ° C. for 3 hours, hydrolyzed with ice water at −30 ° C. and extracted with EtOAc. The organic layer was separated, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue (1.5 g) was purified by column chromatography on silica gel (SiO ₂ 15-40 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 99/1 / 0.1). Pure fractions were combined and the solvent was evaporated. The product was crystallized with methanol to afford 0.087 g of compound 36 (6%, mp = 190 ° C.) (diastereo isomer A) and 0.088 g of compound 5 (6%, mp = 140 ° C.) (diastereo isomer B). .

b. Preparation of Compound 30

Follow the procedure for compound 5, but use intermediates 6 (prepared according to A3) and 3- (dimethylamino) -1- (1-naphthalenyl) -1-propanone as starting material as in the procedure for compound 5 Thus, compound 30 was prepared. Yield: 0.087 g of compound 30 (diastereo isomer B) (5%; m. P. = 210 ° C.).

Example B4

Preparation of Compounds 15 and 16

Tetrabutylammonium bromide (TBAB 1 M in THF, 1.45 ml, 1.45 mmol) was added dropwise at 0 ° C. to a solution of intermediate 8 (prepared according to A4.b) (0.46 g, 0.72 mmol) in THF (5 ml). . The mixture was stirred at rt for 2 h, then poured into 10% aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue (0.45 g) was purified by column chromatography on silica gel (Sunfire 5 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 98/2 / 0.2). Pure fractions were combined and the solvent was evaporated. Yield: 0.014 g of compound 15 (4%, mp = 205 ° C).

Compound 16 was prepared following the same procedure as compound 15, but using Intermediate 9 (prepared according to A4.b) as a starting material. Yield: 0.037 g of compound 16 (7%).

Example B5

Preparation of Compounds 17, 18, 19 and 20

A solution of intermediate 13 (prepared according to A2.a-3) (enantiomer A2, 2.0 g, 3.96 mmol) in NH ₃ / MeOH (7 N, 40 ml) was stirred at room temperature for 18 hours, and then Pd / C (10% anhydrous, 2.0 g) was added. The resulting suspension was placed under 4 bar H ₂ and stirred for 24 hours. The mixture was filtered through a short pad of celite and the solvent was evaporated to dryness. The residue (2.0 g) was purified by column chromatography on silica gel (SiO ₂ 15-40 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 93/7 / 0.5). Pure fractions were combined and the solvent was evaporated. Yield: 0.40 g of Compound 19 (A2; 1S, 2R; 20%).

Depending on the same procedure as compound 19, compound 17 (diastereoisomer A) was prepared using intermediate 10 (prepared according to A2.a-3) as starting material. Yield: 0.083 g of compound 17 (8%, m.p. = 180 ° C).

Following the same procedure as compound 19, starting with intermediate 11 (prepared according to A2.a-3), compound 20 (diastereoisomer B) was prepared. Yield: 0.06 g of Compound 20 (20%, m.p. = 184 ° C).

Compound 18 (A1; 1R, S2) was prepared following the same procedure as compound 19, but using Intermediate 12 (prepared according to A2.a-3) as a starting material. Yield: 0.73 g of compound 18 (19%).

Example B6

Preparation of Compound 29

Intermediate 10 (prepared according to A3.a-3) (diastereoisomer A) (0.0002 mol) and methylpiperazine (0.0007 mol) in CH ₃ CN (3 ml), THF (3 ml) and AcOH (0.15 ml) ) Was stirred at room temperature for 2 hours. BH ₃ CN (polymer support) (0.0003 mol) was added followed by CH ₃ CN (0.0003 mol). The mixture was stirred at rt for 48 h, poured into H ₂ O and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98/2 / 0.2 to 92/8 / 0.8; 5 μm). Pure fractions were combined and the solvent was evaporated. Yield: 0.021 g of compound 29 (12%).

Example B7

Preparation of Compounds 21 and 22

Sodium cyanoborohydride (0.056 g, 8.9 mmol) was added to compound 17 (prepared according to B5) (0.15 g, 0.30 mmol) in acetonitrile (3 ml), 30% formaldehyde (0.24 ml, 3.0 mmol) in water. And a solution of acetic acid (0.15 ml). The reaction mixture was stirred at rt for 48 h and poured into water. The organic layer was extracted with AcOEt, washed with brine, dried over MgSO ₄ , filtered, evaporated and dried. The residue (0.18 g) was purified by silica gel (Sunfire 5 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 98/2 / 0.2 to CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 94 /6/0.6) on column chromatography. Pure fractions were combined and the solvent was evaporated. Yield: 0.07 g of compound 21 (44%).

Following the same procedure as compound 21, compound 22 (diastereo isomer B) was prepared using compound 20 (diastereo isomer B) (prepared according to B5) as a starting material. Yield: 0.063 g of compound 22 (40%).

Example B8

Preparation of Compound 27

A solution of compound 20 (prepared according to B5) (80 mg, 0.158 mmol), acetyl chloride (0.011 ml, 0.158 mmol) and triethylamine (0.024 ml, 0.174 mmol) in CH ₂ Cl ₂ (5 ml) was room temperature Stirred for 24 h. The mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was washed with water, dried over MgSO ₄ , filtered, evaporated to dryness. The residue (0.14 g) was purified by silica gel (Sunfire 5 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 98/2 / 0.2 to CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 94 /6/0.6) on column chromatography. Pure fractions were combined and the solvent was evaporated. Yield: 0.084 g of compound 27 (97%, mp = 203 ° C.).

Example B9

a. Preparation of Compound 28

Intermediate 7 in THF (2 ml) and CH ₂ Cl ₂ (2 ml) (made according to A4.a) (0.15 g, 0.288 mol), dimethylamine hydrochloride (0.047 g, 0.576 mol), hydroxybenzotria A solution of sol (0.047 g, 0.346 mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.066 g, 0.346 mol), triethylamine (0.081 ml, 0.576 mol) was stirred at room temperature After stirring for 18 hours, it was poured into water. The organic layer was extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered and evaporated to dryness. The residue (0.15 g) was purified by column chromatography on silica gel (Chromasil 5 μm, eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH: 99/1 / 0.1). Pure fractions were combined and the solvent was evaporated. Yield: 0.010 g of compound 28 (64%).

b. Preparation of Compound 31

Following the procedure for compound 28, compound 31 was prepared, using Intermediate 7 (prepared according to A4.a) and 1-methylpiperazine as starting materials. Yield: 0.039 g of compound 31 (diastereo isomer A) (39%; m.p. = 195 ° C).

Example  B10

a. Preparation of Compound 37

N-BuLi 1.6 M (1.4 ml, 0.018 mol) in hexane was added to 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl in THF (10 mol). was added to a solution of -β-phenyl-3-quinolineethanol (a mixture of diastereoisomers A, RS and SR; compound 14 of WO 2004/011436) (0.5 g, 0.009 mol) and cooled to -70 ° C under N ₂ atmosphere. It was. The mixture was stirred at -70 [deg.] C. for 2 hours, then a solution of N-methyl-N-methoxybenzamide (0.3 g, 0.0018 mol) in THF (2.5 ml) was added dropwise. The reaction mixture was stirred at −70 ° C. for 3 hours and then diluted with water. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by SFC chiral chromatography (ChiralPakADH 5 μm, eluent: CO ₂ / MeOH 10 / iPA: 92/8 / 0.5). Yield: 63 mg of compound 37 (13%).

b. Preparation of Compounds 38 and 39

Manganese oxide (0.11 g) was added portionwise to a solution of intermediate 16 (prepared according to A5.a) (0.11 g, 0.166 mmol) in CH ₂ Cl ₂ (5 ml) and the reaction mixture was stirred at room temperature for 5 hours. . The resulting solution was filtered through celite and washed with CH ₂ Cl ₂ . The filtrate was concentrated to dryness. The product was crystallized from 2-propanol. Yield: 82 mg of compound 38 (A1; 1R, 2S) (75%, mp = 118 ° C).

Following the procedure for compound 38, compound 39 was prepared, using Intermediate 17 (prepared according to A5.a) as starting material. Yield: 0.030 g of compound 39 (diastereo isomer A) (34%).

c. Preparation of Compound 40

The procedure for compound 38 was followed, but compound 40 was prepared using Intermediate 18 (prepared according to A5.b) as a starting material. Yield: 0.13 g of compound 40 (diastereo isomer B) (36%; m.p. = 185 ° C).

Tables 1-3 show compounds of formula (la) of the invention prepared according to one of the procedures (Example No.) above.

For many compounds, the melting point was determined by a Kofler hot bench consisting of a heating plate with a linear temperature gradient, a sliding pointer and a temperature scale (° C.).

Table 1:

Table 2:

Table 3:

C. Analysis Method

A. LCMS

The mass of some compounds were recorded by LCMS (Liquid Chromatography Mass Spectrometry). The method used is described below.

General Procedure A

Alliance HT, including a quaternary pump with degasser, an autosampler, a diode array detector (DAD), and a column (keeping the column at a temperature of 30 ° C.) as defined in each method below. HPLC measurements were performed using the 2795 (Waters) system. The flow of the column was partitioned with MS analyzer. The MS detector was configured with an electrospray ionization source. On the Time of Flight Zspray ^™ Mass Spectrometer (Waters-for Methods 1, 2, 3 and 4), the capillary needle voltage is 3 kV, the source temperature is maintained at 100 ° C. and ZQ ^{On the TM} (simple quadrupole Zspray ^™ mass spectrometer (Waters)-for methods 5, 6 and 7) the capillary needle voltage was 3.15 kV and the source temperature was maintained at 110 ° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data system.

General procedure B

UPLC (Ultrafast Liquid Chromatography) Acquity, which includes a binary pump with a degasser, an autosampler, a diode array detector (DAD) and a column (keeping the column at a temperature of 40 ° C.) as defined in each method below. LC measurements were performed using a (Waters) system. The flow of the column was raised with an MS detector. The MS detector was configured with an electrospray ionization source. On the Quadto (Triple Quadrupole Mass Spectrometer) (Waters) the capillary needle voltage was 3 kV and the source temperature was maintained at 130 ° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a Waters-Micromass Masrin-Openins data system.

Method 1:

In addition to the general procedure A, reverse phase HPLC was performed on a Chromasyl C18 column (5 μm, 4.6 × 150 mm) at a flow rate of 1.0 ml / min. 30% A, 40% B and 30% in 4 minutes using three mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C: 0.2% formic acid + 99.8% ultrapure water) Gradient conditions were performed at 100% B at C (holding for 1 minute), held at 100% B for 5 minutes, and re-equilibrated to initial conditions for 3 minutes. 5 μl injection volume was used. The cone voltage was 20 V for the positive ionization mode. Mass spectra were obtained by scanning from 100 to 900 times in 0.8 seconds using an interscan delay of 0.08 seconds.

Method 2:

In addition to general procedure A, reverse phase HPLC was performed on an Xterra-MS C18 column (5 μm, 4.6 × 150 mm) at a flow rate of 1.0 ml / min. Using two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile) from 5% to 85% A, 15% B (hold for 3 minutes) to 20% A, 80% B Gradient conditions were performed, held at 20% A and 80% B for 6 minutes and re-equilibrated to initial conditions for 3 minutes. 20 μl injection volume was used. The cone voltage was 20 V for the positive ionization mode. Mass spectra were obtained by scanning from 100 to 900 times in 0.8 seconds using an interscan delay of 0.08 seconds.

Method 3:

In addition to general procedure A, reverse phase HPLC was performed on an Xterra-MS C18 column (5 μm, 4.6 × 150 mm) at a flow rate of 1.0 ml / min. Using two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile) from 5% to 85% A, 15% B (hold for 3 minutes) to 20% A, 80% B Gradient conditions were performed, held at 20% A and 80% B for 6 minutes and re-equilibrated to initial conditions for 3 minutes. 20 μl injection volume was used. The cone voltage was 20 V for positive ionization mode and 20 V for negative ionization mode. Mass spectra were obtained by scanning from 100 to 900 times in 0.8 seconds using an interscan delay of 0.08 seconds.

Method 4:

In addition to the general procedure A, reverse phase HPLC was performed on a Chromasyl C18 column (5 μm, 4.6 × 150 mm) at a flow rate of 1.0 ml / min. 30% A, 40% B and 30% in 4 minutes using three mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C: 0.2% formic acid + 99.8% ultrapure water) Gradient conditions were performed at 100% B at C (holding for 1 minute), held at 100% B for 5 minutes, and re-equilibrated to initial conditions for 3 minutes. 5 μl injection volume was used. The cone voltage was 20 V for positive and negative ionization modes. Mass spectra were obtained by scanning from 100 to 900 times in 0.8 seconds using an interscan delay of 0.08 seconds.

Method 5:

In addition to general procedure A, reverse phase HPLC was performed on a Sunfire C18 column (3.5 μm, 4.6 × 100 mm) at an initial flow rate of 0.8 ml / min. Using 2 mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) 100% A (4 minutes) Gradient) at 100% B, held at 100% B for 4 minutes at a flow rate of 1.2 ml / min, and re-equilibrated to initial conditions for 3 minutes. 10 μl injection volume was used. The cone voltage was 20 V for the positive and negative ionization modes. Mass spectra were obtained by scanning from 100 to 1000 times in 0.4 seconds using an interscan delay of 0.3 seconds.

Method 6:

In addition to general procedure A, reverse phase HPLC was performed on a Sunfire C18 column (3.5 μm, 4.6 × 100 mm) at an initial flow rate of 0.8 ml / min. Using 2 mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) 100% A (4 minutes) Gradient) at 100% B, held at 100% B for 4 minutes at a flow rate of 1.2 ml / min, and re-equilibrated to initial conditions for 3 minutes. 10 μl injection volume was used. Positive ionization mode was used with four different cone voltages (20, 40, 50, 55 V). Mass spectra were obtained by scanning from 100 to 1000 times in 0.4 seconds using an interscan delay of 0.1 seconds.

Method 7:

In addition to general procedure A, reverse phase HPLC was performed on a Sunfire C18 column (3.5 μm, 4.6 × 100 mm) at an initial flow rate of 0.8 ml / min. Using 2 mobile phases (mobile phase A: 25% 7 mM ammonium acetate + 50% acetonitrile + 25% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) 100% A (4 minutes) Gradient) at 100% B, held at 100% B for 4 minutes at a flow rate of 1.2 ml / min, and re-equilibrated to initial conditions for 3 minutes. 10 μl injection volume was used. The cone voltage was 20 V for the positive and negative ionization modes. Mass spectra were obtained by scanning from 100 to 1000 times in 0.4 seconds using an interscan delay of 0.3 seconds.

Method 8:

In addition to general procedure B, reverse phase UPLC was performed on a Waters Acquity crosslinked ethylsiloxane / silica hybrid (BEH) C18 column (1.7 μm, 2.1 × 100 mm) at a flow rate of 0.4 ml / min. Using two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile) from 3.5% 80% A and 20% B (hold 0.5 minutes) to 10% A and 90% B Gradient conditions were performed, held for 2 minutes, and re-equilibrated to initial conditions for 2 minutes. 2 μl injection volume was used. The cone voltage was 20, 30, 45, 60 V for the positive ionization mode. Mass spectra were obtained by scanning from 100 to 1000 times in 0.2 seconds using an interscan delay of 0.1 seconds.

If the compound is a mixture of isomers giving different peaks in the LCMS method, only the residence time of the main component is given in the LCMS table

Table 4: LCMS: (MH ⁺ ), protonated molecular ions (of free base), and retention time (R _t (min))

B. Light Rotation

Optical rotation was measured using a polarimeter. [α] _D ²⁰ represents the optical rotation measured by light at the D-ray wavelength (589 nm) of sodium at a temperature of 20 ° C. The cell path length is 1 dm. Actual values describe the concentration and solvent of the solution used to measure the optical rotation.

Table 5: Light Rotational Speed Data

D. Pharmacological Examples

D.1. M. tuberculosis In vitro method for testing of compounds for

Sterile 96-well plastic microtiter plates were filled with 100 μl Middlebrook (1 ×) broth medium. Compound stock (10 × final test concentration) was then added to a series of duplicate wells in column 2 at a dose of 25 μl so that its efficacy on bacterial growth could be assessed. A series of 5-fold dilutions were prepared directly on microtiter plates in columns 2-11 using custom robotic systems (Zymark Corp., Hopkinton, Mass.). Pipette tips were exchanged after every three dilutions to minimize pipetting errors with highly hydrophobic compounds. Untreated control samples containing inoculum (column 1) and no inoculum (column 12) were included in each microtiter plate. Approximately 5000 CFU / well of Mycobacterium tuberculosis (strain H37RV) was added to columns A through H except column 12 at a dose of 100 μl in Middlebrook (1 ×) broth medium. Equal amounts of broth medium without inoculum were added to columns 12 in columns A through H. Cultures were incubated at 37 ° C. for 7 days in a humid atmosphere (incubator with open atmospheric valves and continuously ventilated). Six days after inoculation, one day prior to incubation, Resazurin (1: 5) was added to all wells at a dose of 20 μl and the microtiter plate was further incubated at 37 ° C. for 24 hours. On day 7 bacterial growth was measured by immunofluorescence.

Fluorescence was read at a excitation wavelength of 530 nm and emission wavelength of 590 nm on a computer-controlled fluorometer (Spectramax Gemini EM, Molecular Devices). The percent growth inhibition achieved by the compound was calculated according to standard methods and expressed as IC ₉₀ (μg / ml), defined as the 90% inhibitory concentration for bacterial growth. The results are shown in Table 6.

D.2. In vitro method for testing compounds for antibacterial activity against strain M. Smegmatis ATCC607

Sterile 96-well plastic microtiter plates were filled with 180 μl of deionized water and supplemented with 0.25% BSA. Compound stock (7.8 × final test concentration) was then added to a series of duplicate wells in column 2 at a dose of 45 μl to assess its efficacy on bacterial growth. A series of 5-fold dilutions (45 μl in 180 μl) were prepared directly in microtiter plates of columns 2-11 using a custom robot system (Zymark Corp., Hopkinton, Mass.). Pipette tips were exchanged after every three dilutions to minimize pipetting errors with highly hydrophobic compounds. Untreated control samples containing inoculum (column 1) and no inoculum (column 12) were included in each microtiter plate. Approximately 250 CFU / well of bacterial inoculum was added to columns A through H except column 12 at a dose of 100 μl in 2.8 × Mueller-Hinton broth medium. Equal amounts of broth medium without inoculum were added to columns 12 in columns A through H. Cultures were incubated at 37 ° C. for 48 hours in a 5% CO ₂ wet atmosphere (incubator with open air valve and continuously ventilated). Two days after the incubation was over, the bacterial growth was quantified by immunofluorescence. Accordingly, Alamar Blue (10 ×) was added to all wells at a dose of 20 μl and the microtiter plate was incubated at 50 ° C. for 2 more hours.

Fluorescence was read (30 gains) with an excitation wavelength of 530 nm and emission wavelength of 590 nm in a computer-controlled fluorometer (Cytofluor, Biosearch). Percent proliferation inhibition achieved by the compound was calculated according to standard methods and expressed as IC ₉₀ (μg / ml), defined as the 90% inhibitory concentration for bacterial growth. The results are shown in Table 6.

D.3. In vitro methods for testing compounds for antibacterial activity against various nonmycobacteria

Preparation of Bacterial Suspensions for Susceptibility Testing:

The bacteria used in this study were grown overnight with stirring at 37 ° C. in a flask containing 100 ml Mueller-Hinton broth (Becton Dickinson-catalog No. 275730) in sterile deionized water. Stock (0.5 mL / tube) was stored at −70 ° C. until use. Bacterial titers were performed on microtiter plates to detect TCID ₅₀ , where TCID ₅₀ represents the dilution that caused bacterial growth to 50% of the inoculation medium.

In general, an inoculum level of approximately 100 TCID ₅₀ was used for the sensitivity test.

Antibacterial Susceptibility Test: IC ₉₀  Measure

Microtiter Plate Analysis

Sterile 96-well plastic microtiter plates were filled with 180 μl of sterile deionized water supplemented with 0.25% BSA. A stock solution of the compound (7.8 × final test concentration) was then added to column 2 in 45 μl volume. Serial 5-fold dilutions (45 μl in 180 μl) were prepared directly on microtiter plates from column 2 to column 11. An untreated control sample (column 1) containing an inoculum and an untreated control sample (column 12) without it was included in each microtiter plate. Depending on the type of bacteria, about 10-60 CFU / well of bacterial inoculum (100 TCID50) was added to columns A-H except column 12 in a volume of 100 μl in 2.8 × Müller-Hinton broth medium. Equal amounts of broth medium without inoculum were added to columns 12 in columns A through H. The cultures were incubated at 37 ° C. for 24 hours in normal atmosphere (incubator with open air valve and continuously ventilated). After incubation and one day after inoculation, bacterial growth was measured by immunofluorescence. Thus, 3 hours after inoculation, resazurin (0.6 mg / ml) was added to all wells at a dose of 20 μl and the microtiter plate was reincubated overnight. There was bacterial growth as the color changed from blue to pink. Fluorescence was read at an excitation wavelength of 530 nm and emission wavelength of 590 nm on a computer-controlled fluorometer (Cytofluor Biosearch). The percent inhibition of growth achieved by the compound was calculated according to standard methods. IC ₉₀ (expressed in μg / ml) is defined as the 90% inhibitory concentration on bacterial growth. The results are shown in Table 6.

Agar dilution method

MIC ₉₉ levels (minimum concentrations to achieve 99% inhibition of bacterial growth) can be measured by performing standard agar dilution methods according to the NCCLS standard ^* , wherein the medium used comprises Müller-Hinton agar.

^* Clinical laboratory strandard institute. 2005. Methods for dilution Antimicrobial susceptibility tests for bacteria that grows Aerobically; Revised Standard-Sixth Edition.

Time kill assays

The bactericidal or bacteriostatic activity of the compounds can be measured by time kill analysis using the broth microdilution method ^* . In time kill assays for Staphylococcus aureus and methicillin resistant S. aureus (MRSA), the starting inoculum of S. aurues and MRSA is 10 ⁶ CFU / mL in Mueller Hinton broth. Antibacterial compounds were used at concentrations of 0.1 to 10 fold MIC (ie IC ₉₀ determined in microtiter plate assay). Wells not provided with antibacterial agent consisted of culture propagation control. Plates containing microorganisms and test compounds were incubated at 37 ° C. After 0, 4, 24 and 48 hours of inoculation, samples were serially diluted (10 ⁻¹ to 10 ⁻⁶ ) in sterile PBS to remove viability coefficients and plated (200 μl) on Muller Hinton agar. Plates were incubated at 37 ° C. for 24 hours and colony counts measured. Death curves can be plotted by plotting log ₁₀ CFU per ml over time. Bactericidal effects are usually defined as a 3-log ₁₀ reduction in CFU number per ml compared to untreated inoculum. Colonies were counted at the highest dilution used for a series of dilutions and platings to remove any potential residual drug.

^* Zurenko, GE et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother . 40 , 839-845 (1996).

Measurement of ATP Levels in Cells

To analyze changes in total cell ATP concentrations (using ATP bioluminescence kit, Roche), S. aureus (ATCC29213) stock cultures were grown in 100 ml of Mueller Hinton flasks and stirred-incubator for 24 hours at 37 ° C. Analysis was performed by incubation at 300 rpm). OD ₄₀₅ nm was measured and CFU / mL was calculated. Cultures were diluted to 1 × 10 ⁶ CFU / mL (final concentration for ATP measurement: 1 × 10 ⁵ CFU / 100 μl per well) and compounds added at 0.1-10 fold MIC (ie IC ₉₀ determined in microtiter plate assay). These tubes were incubated at 37 ° C. at 300 rpm for 0, 30, 60 minutes. A 0.6 ml bacterial suspension from the snap-cap tube was used and added to a new 2 ml eppendorf tube. 0.6 ml of cell lysate was added (Roche kit), vortexed at maximum speed, and incubated at room temperature for 5 minutes. Cooled on ice. The luminometer was warmed to 30 ° C. (Luminoskan Ascent Labsystems with injector). One column (= 6 wells) was filled with 100 μl of the same sample. 100 μl of luciferase reagent was added to each well using an injector system. Luminescence was measured for 1 second.

Table 6: IC ₉₀ Values (μg / mL)

ECO 35218 means Escherichia coli (ATCC35218); EFA 29212 means Enterococcus faecalis (ATCC29212); PAE 27853 means Pseudomonas aeruginosa (ATCC27853); SPN 6305 means Streptococcus pneumoniae (ATCC6305); SPY 8668 is known as Streptococcus pyogens (ATCC8668); STA 29213 means Staphylococcus aureus (ATCC29213); MSM 607 means M. Smegmatis (ATCC607); MTB H37RV Mycobacterium means tuberculosis (strain H37RV); ATCC stands for American type tissue culture.

Claims (28)

Compounds of formula (la) or (lb), or stereochemically isomeric, N-oxide forms, pharmaceutically acceptable salts or solvates thereof: Where q is an integer of 0, 1, 2, 3 or 4; p is an integer of 1, 2, 3 or 4; R ¹ is alkenyl, alkynyl, -C = N-OR ¹¹ , amino, mono or di (alkyl) amino, aminoalkyl, mono or di (alkyl) aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl, mono Or di (alkyl) aminocarbonyl, arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-; R ² is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino, pyrrolidino or a radical of the formula: , Wherein Y is CH ₂ , O, S, NH or N-alkyl; R ³ is alkyl, arylalkyl, aryl-O-alkyl, aryl-alkyl-O-alkyl, aryl, Het, Het-alkyl, Het-O-alkyl, Het-alkyl-O-alkyl or Is; R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; R ⁴ and R ⁵ together with N to which they are attached include alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl And pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, already optionally substituted with pyrimidinyl Consisting of dazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Can form radicals selected from the group; R ^4a and R ^5a together with the nitrogen atom to which they are attached are alkyl, haloalkyl, halo, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, Pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2, optionally substituted by 1, 2, 3 or 4 substituents independently selected from pyridyl or pyrimidinyl 3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azinyl, hexahydro-1H-1,4- Diazepinyl, hexahydro-1,4-oxazepineyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2- Consisting of imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl Form a radical selected from the group, and; R ⁶ is aryl ¹ or Het; R ⁷ is hydrogen, halo, alkyl, aryl or Het; R ⁸ is hydrogen or alkyl; R ⁹ is oxo; R ⁸ and R ⁹ together form a radical —CH═CH—N =; R ¹¹ is hydrogen or alkyl; Aryl is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono Or a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from dialkylaminocarbonyl; Aryl ¹ is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, alkylthio, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, mor A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from polyyl, Het or mono- or dialkylaminocarbonyl; Het is N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl Monocyclic heterocycles selected from pyrazinyl or pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [ Bicyclic heterocycle selected from 1,4] dioxylyl or benzo [1,3] dioxolyl; Wherein each monocyclic and bicyclic heterocycle is optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, alkyl or alkyloxy. The compound of claim 1, wherein R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, —C═N—OR ¹¹ , amino, mono or di (C _1-6 alkyl) amino, aminoC _1-6 Alkyl, mono or di (C _1-6 alkyl) aminoC _1-6 alkyl, C _1-6 alkylcarbonylaminoC _1-6 alkyl, aminocarbonyl, mono or di (C _1-6 alkyl) aminocarbonyl , Arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (═O) —; R ² is hydrogen, C _1-6 alkyloxy, aryl, aryloxy, hydroxy, mercapto, C _1-6 alkyloxyC _1-6 alkyloxy, C _1-6 alkylthio, mono or di (C _{1- 6} alkyl) amino, pyrrolidino or a radical of the formula , Wherein Y is CH ₂ , O, S, NH or NC _1-6 alkyl; R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, aryl C _1-6 alkyl, aryl, -OC _1-6 alkyl, aryl C _1-6 -OC _1-6 alkyl, aryl, Het, Het-C _1-6 alkyl, Het-OC _1-6 alkyl, HetC _1-6 alkyl-OC _1-6 alkyl or Is; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or benzyl; And R ⁴ and R ⁵ together with N to which they are attached, include C _1-6 alkyl, halo, haloC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, amino, mono- or di ( Pyrrolidinyl optionally substituted with C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkylthioC _1-6 alkyl and pyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl A radical selected from the group consisting of pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl; R ^4a and R ^5a together with the nitrogen atom to which they are attached are each C _1-6 alkyl, polyhaloC _1-6 alkyl, halo, arylC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, C _1-6 alkyloxyC _1-6 alkyl, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 AlkylthioC _1-6 pyrrolidino, piperidino, piperazino, morpholino optionally substituted by 1, 2, 3 or 4 substituents independently selected from alkyl, aryl, pyridyl or pyrimidinyl , 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azinyl , Hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imi Dazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazole , Triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, form a radical selected from the group consisting of pyrazinyl and triazinyl, and; R ⁶ is aryl ¹ or Het; R ⁷ is hydrogen, halo, C _1-6 alkyl, aryl or Het; R ⁸ is hydrogen or C _1-6 alkyl; R ⁹ is oxo; R ⁸ and R ⁹ together form a radical —CH═CH—N =; R ¹¹ is hydrogen or C _1-6 alkyl; Aryl is hydroxy, halo, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy, 1, 2 or independently selected from haloC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or di (C _1-6 alkyl) aminocarbonyl A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by three substituents; Aryl ¹ is hydroxy, halo, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy , C _1-6 alkylthio, haloC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl, Het or mono- or di (C _1-6 alkyl) aminocarbon A homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl optionally substituted by 1, 2 or 3 substituents independently selected from niyl; Het is N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl Monocyclic heterocycles selected from pyrazinyl or pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [ Bicyclic heterocycle selected from 1,4] dioxylyl or benzo [1,3] dioxolyl; Wherein each monocyclic and bicyclic heterocycle is optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkyloxy Compound. 3. A method according to claim 1 or 2 wherein, R ¹ is C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, -C = N-OR ^11, amino, mono or di (C _{1 - 6} alkyl) amino, amino C _{1 - 6} alkyl, mono or di (C _1-6 alkyl) amino C _1-6 alkyl, C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 6} alkyl, aminocarbonyl, mono- or di (C _1-6 alkyl Aminocarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-. 4. A compound of claim 3, wherein R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, -C = N-OR ¹¹ , R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC And (= O)-. The compound of claim 4, wherein R ¹ is C _2-6 alkenyl or —C═N—OR ¹¹ . The compound of any of claims 1-5, wherein p is 1. 7. 7. Compounds according to any of claims 1 to 6, wherein R ² is C _1-6 alkyloxy. The method of claim 7 wherein, R ² is a compound which is characterized in that methyloxy. The compound of any of claims 1-8, wherein R ³ is arylC _1-6 alkyl or aryl. 10. The compound of any one of claims 1-9, wherein q is 1 or 3. The compound of any of claims 1-10, wherein R ⁴ and R ⁵ represent C _1-6 alkyl. The compound according to any one of claims 1 to 10, wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a piperidino. 13. Compounds according to any one of claims 1 to 12, wherein R ⁶ is phenyl optionally substituted with halo. 14. Compounds according to any one of claims 1 to 13, wherein R ⁷ is hydrogen. The compound according to any one of claims 1 to 14, which is a compound of formula (la). The compound of claim 1, wherein R ¹ is C _2-6 alkenyl, C _2-6 alkynyl, —C═N—OR ¹¹ , amino, aminoC _1-6 alkyl, mono or di (C _1-6 alkyl) AminoC _1-6 alkyl, C _1-6 alkylcarbonylaminoC _1-6 alkyl, mono or di (C _1-6 alkyl) aminocarbonyl, arylcarbonyl, R ^5a R ^4a Nalkyl, R ^5a R ^4a N- or R ^5a R ^4a NC (= 0)-; R ² is alkyloxy; R ³ is arylalkyl or aryl; R ⁴ and R ⁵ are C _1-6 alkyl; R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a piperidino; R ⁶ is phenyl optionally substituted with halo; R ⁷ is hydrogen; R ¹¹ is hydrogen or C _{1 - 4} alkyl and; q is 1 or 3; A compound of formula (Ia) wherein p is 1; The compound according to any one of claims 1 to 16, for use as a medicament. The compound according to any one of claims 1 to 16, for use as a medicament for the treatment of bacterial infections, including mycobacterial infections. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 to 16 as the active ingredient. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the treatment of bacterial infections. The use of claim 20, wherein the bacterial infection is an infection caused by Gram-positive bacteria. 22. The use according to claim 21, wherein the Gram-positive bacteria is Streptococcus pneumoniae . Use according to claim 21, wherein the Gram-positive bacteria is Staphylococcus aureus . Compound of formula (VIII-a): Wherein W ₂ represents a suitable leaving group. Compound of Formula (VIII-b): Wherein W ₂ represents a suitable leaving group. a) a suitable catalyst and in the presence of a suitable solvent, W ₁ is the intermediate of formula (II-a) or (II-b) represents a suitable leaving tributyl (C _{2 - 6} alkenyl) tin, and reaction to, or: Wherein all variables are as defined in claim 1; b) reacting an intermediate of formula (II-a) or (II-b) with R ^5a R ^4a NH in the presence of a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent, wherein W ₁ represents a suitable leaving group: Wherein all variables are as defined in claim 1; c) reacting intermediates of formula (III-a) or (III-b) with hydroxylamine hydrochloride or C _1-6 alkoxylamine hydrochloride in the presence of a suitable solvent: Wherein all variables are as defined in claim 1; d) reducing the intermediate of formula (III-a) or (III-b) in the presence of H ₂ , a suitable catalyst and a suitable solvent: Wherein all variables are as defined in claim 1; e) reacting the intermediate of formula (III-a) or (III-b) with formula R ^5a R ^4a NH in the presence of a suitable reducing agent, a suitable solvent and a suitable acid: Wherein all variables are as defined in claim 1; f) reacting the intermediate of formula (IV-a) or (IV-b) with diphenylphosphoryl azide (DPPA) and a suitable base in a suitable solvent, followed by addition of trimethylsilylethanol to add the product thus obtained Or react with tetrabutylammonium bromide (TBAB) in a suitable solvent with: Wherein all variables are as defined in claim 1; g) reaction of the intermediate of formula (IV-a) or (IV-b) with an appropriate amine, hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, suitable base and suitable solvent Or: Wherein R ^1a represents aminocarbonyl, mono or di (alkyl) aminocarbonyl or R ^5a R ^4a NC (═O) —, all variables being as defined in claim 1; h) reacting the intermediate of formula (II-a) or (II-b) with the appropriate arylaldehyde in the first step (a) in the presence of n-BuLi and a suitable solvent, followed by step (a Or oxidize the product obtained in Wherein all variables are as defined in claim 1; i) reacting the intermediate of formula (Va) or (Vb) with the intermediate of formula (VI) in a mixture of a suitable base with a suitable solvent in the presence of n-BuLi: Wherein all variables are as defined in claim 1; j) Formula (VII) wherein q 'is 0, 1 or 2 in the presence of a suitable catalyst, optionally in the presence of a second catalyst (for reduction), a suitable ligand and a suitable solvent, in the presence of CO and H ₂ (under pressure) -a) or the intermediate of (VII-b) is reacted with primary or secondary amine HNR ⁴ R ⁵ : Wherein all variables are as defined in claim 1; k) optionally reacting an intermediate of formula (VIII-a) or (VIII-b) with a primary or secondary amine HNR ⁴ R ^{5 in} the presence of a suitable solvent, wherein W ₂ represents a suitable leaving group: Wherein all variables are as defined in claim 1; If necessary, according to transformations known in the art, the compounds of formula (Ia) or (Ib) are converted to each other and further, if necessary, the compounds of formula (Ia) or (Ib) are treated with an acid for treatment. Conversion to an active non-toxic acid addition salt, or treatment with base to a therapeutically active non-toxic base addition salt, or conversely with alkali to convert an acid addition salt form to a free base, or to acid Treating to convert the base addition salt to the free acid and, if necessary, to prepare its stereochemically isomeric, quaternary amine or N-oxide form. A combination of (a) the compound of any one of claims 1 to 16 with (b) at least one other antimicrobial agent. A product containing (a) the compound of any one of claims 1 to 16 and (b) at least one other antimicrobial agent as a formulated formulation for simultaneous, separate or sequential use in the treatment of a bacterial infection.